2-,3-,4-,5-,6-,7-,8-,9- and/or 10-substituted dibenzoxazepine and dibenzthiazepine compounds, pharmaceutical compositions and methods of use

ABSTRACT

The present invention provides substituted dibenzoxazepine and dibenzthiazepine compounds of Formula I: ##STR1## which are useful as analgesic agents for the treatment of pain, and for prostaglandin-E 2  mediated diseases, pharmaceutical compositions comprising a therapeutically-effective amount of a compound of Formula I in combination with a pharmaceutically-acceptable carrier, a method for eliminating or ameliorating pain in an animal comprising administering a therapeutically-effective amount of a compound of Formula I to the animal, and a method for treating prostaglandin-E 2  mediated diseases in an animal comprising administering a therapeutically-effective amount of a compound of Formula I to the animal.

This Application is a Continuation-In-Part Application of applicationU.S. Ser. No. 08/079,021, filed on Jun. 16, 1993, now U.S. Pat. No.5,354,747.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention generally relates to compounds havingpharmacological activity which are useful as pharmaceutical agents and,more particularly, as analgesic agents for the treatment of pain, topharmaceutical compositions containing one or more of these compounds,and to methods of treatment employing these compounds. Moreparticularly, the present invention concerns substituted dibenzoxazepinecompounds, pharmaceutical compositions containing one or more of thesecompounds in combination with a pharmaceutically-acceptable carrier, andmedical methods of treating pain employing these compounds.

Analgesic compounds are agents which alleviate pain without causing aloss of consciousness and, thus, which are useful for treating pain and,often, for reducing inflammation.

The major classes of analgesic compounds include narcotic analgesics, oropiates, compounds which alleviate pain and induce sleep, andanalgesic-antipyretic compounds, compounds which alleviate pain andreduce fever, such as salicylates.

Although the efficacy of opiates in relieving pain is well established,the associated addiction liability of opiates is a distinct disadvantageof these compounds.

While salicylate and salicylate-like agents (non-steroidalantiinflammatory agents or NSAIDS) are also efficacious in relievingpain, they often exhibit undesirable side effects, such asgastrointestinal irritation, as with aspirin, allergic response, as withaspirin, and/or liver toxicity with extended use, as with acetaminophen.

The compounds of the present invention are neither opiates norsalicylates, and represent another class of compounds which are usefulas analgesic agents.

(2) Description of the Related Art

U.S. Pat. No. 3,357,998 discloses amides ofdihydrodibenzo[b,f][1,4]oxazepine-10-carboxylic acids.

U.S. Pat. No. 3,644,346 discloses semicarbazones ofdibenzoxazepine-N-carboxylic acid hydrazides.

U.S. Pat. No. 4,221,715 discloses dibenz[b,f][1,4]oxazepine-11-ylpyridinium salts and derivatives thereof.

U.S. Pat. No. 4,434,171 discloses5,6-dihydro-5-(4-piperidinyl)-11H-dibenz[b,e]azepines.

U.S. Pat. No. 4,360,525 discloses10-(4-piperidinyl)-10,11-dihydro-dibenz[b,f][1,4]oxazepines,-dibenzo[b,f][1,4]thiazepines and -5H-dibenzo[b,e][1,4]diazepines.

U. S. Pat. No. 4,379,150 discloses dibenz[b,f][1,4]-oxazepinederivatives which are substituted at the 10-position with the group--A--NR₄ R₅, wherein A is a lower alkylene group, and wherein R₄ and R₅may be taken together with a nitrogen atom to form a heterocyclic ring.

European Patent Application Publication Nos. 0 534 667 A1 and 0 480 641A1 disclose tricyclic heterocycles which are stated to counteract mildto moderate pain by virtue of their anti-hyperalgesic properties.

German Patent Application Publication No. 1,170,322 disclosesdibenz[b,f][1,4]oxazepine-11(10H)-ones which are substituted at the10-position with the group --A--CO--NR₅ R₆, wherein A may be a saturatedaliphatic hydrocarbon group, and wherein R₅ and R₆ may representcycloalkyl.

CH 648-309-A discloses N-methyl-piperidinyl dibenzazepine derivativesfor use as neuroleptics, antidepressants and hypnotics.

K Nagarajan et al., "Synthesis of10,11-Dihydrodibenz-[b,f][1,4]oxazepine Derivatives as PotentialAnticonvulsants & Psychotropic Agents,"Indian Journal of Chemistry, 24B,840-844 (1985), disclose the synthesis of acyl, carbamoyl andthiocarbamoyl derivatives of 10,11-dihydrodibenz[b,f][1,4]oxazepine,most of which have either a nitro or an amino group at position-2, asanalogues of carbamazepine, and the evaluation of these derivatives asanticonvulsants associated with neuroleptic activity.

W. E. Coyne et al , "Anticonvulsant Semicarbazides," J. Med. Chem.,11(6), 1158-1160 (1968), disclose the investigation of thestructure-activity relationship of the anticonvulsant activity of aseries of semicarbazides which was synthesized from various tricyclicamines (see Table I, Page 1160).

Margaret E. Greig et al., "Effects of a Group of Dibenzodiazepines onFatal Systemic Anaphylaxis in Mice, Rats and Guinea Pigs," J. Med.Chem., 14(2), 153-153 (1970), discloses a series of dibenzodiazepineswhich was tested for protection against fatal systemic anaphalaxis inmice, rats and guinea pigs.

Each of the documents described hereinabove discloses compounds whichare structurally different from the compounds of the present invention.Thus, the compounds of the present invention are structurally distinctfrom that which has been described in the art.

Compounds within the present invention have been found to exhibitactivity as prostaglandin E₂ antagonists, and have been found to havefew side effects, and no potential for the release of hydrazine, whichis toxic.

SUMMARY OF THE INVENTION

The present invention provides compounds having a structure of FormulaI: ##STR2## or a pharmaceutically-acceptable salt thereof, wherein: X isoxygen, sulfur, ##STR3## Y is hydrogen, halogen or hydroxy; Z ishydrogen or halogen;

A is alkylene or carbonyl;

B is --CH or nitrogen;

D is carbon or nitrogen;

is alkylene, carbonyl, alkyleneamino or alkylenecarbonyl;

G is hydrogen, alkyl, cycloalkyl, alkoxy, aminoalkyl, aminocycloalkyl,aryl, alkylaryl or aryl-substituted aryl;

R is hydrogen or --CO₂ R¹ ;

R¹ is hydrogen or alkyl;

m is an integer of from 0 to 4;

n is an integer of from 0 to 4;

r is 0 or 1;

q is an integer of from 0 to 1;

t is an integer of from 0 to 1; and

p is an integer of from 0 to 1;

with the proviso that B and D cannot both be --CH, with the proviso thatB cannot be --CH when p is 0 and G is alkyl, with the proviso that m andn are not each 0, with the proviso that G is not alkyl or cycloalkylwhen X is sulfur, A is alkylene, B is --CH and D is nitrogen, with theproviso that G is not aminoalkyl or aminocycloalkyl when X is oxygen orsulfur, A is alkylene, B is nitrogen, R is hydrogen, D is carbon, r is 1and p is 0.

The present invention also provides pharmaceutical compositions whichare pharmaceutically acceptable and which comprise atherapeutically-effective amount of a compound of Formula I incombination with a pharmaceutically-acceptable carrier, and a method foreliminating or ameliorating pain in an animal comprising administering atherapeutically-effective amount of a compound of Formula I to theanimal.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For purposes of clarity, the terms and phrases used throughout thisspecification and the appended claims are defined in the manner setforth directly below.

Some of the chemical structures which are presented in thisspecification and the appended claims have been drawn using theconvention which employs lines to represent alkyl radicals, which isknown by those of skill in the art.

The abbreviations "AcOH" and "HOAc" as used herein mean acetic acid.

The term "alkyl" as used herein means a saturated hydrocarbon radicalhaving from one to ten carbon atoms, and within which includes from oneto six carbon atoms, and further within which includes from one to threecarbon atoms, which can be a straight or branched chain. Representativeof such radicals are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, pentyl and the like.

The term "alkylene" as used herein means a straight or branchedsaturated hydrocarbon chain spacer arm which has from one to ten carbonatoms, and within which includes from one to six carbon atoms, andfurther within which includes one, two or three carbon atoms.

The term "alkyleneamino" as used herein means an alkylene group, asdefined above, having an --NH-- group attached thereto.

The term "alkylenecarbonyl" as used herein means an alkylene group, asdefined above, having a carbonyl group attached thereto, as definedbelow.

The term "alkylaryl" as used herein means an alkyl group, as definedabove, having an aryl group, as defined below, attached thereto.

The term "alkoxy" as used herein means an alkyl group, as defined above,having an oxygen atom attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The abbreviation "AlMe₃ " as used herein means trimethylaluminum.

The term "amino" as used herein means an --NH₂ group.

The term "aminoalkyl" as used herein means an amino group, as definedabove, having one or two alkyl groups attached thereto. Representativeaminoalkyl groups include aminomethyl, aminoethyl, aminopropyl,aminobutyl, aminopentyl and the like.

The term "aminocycloalkyl" as used herein means a cycloalkyl group, asdefined below, which has a nitrogen atom, attached thereto.

The term "analgesia" as used herein means the reduction, or absence, ofsensibility to pain, designating particularly the relief of pain withoutloss of consciousness.

The term "animal" as used herein includes mammals and nonmammals, andfurther includes humans and non-human mammals.

The term "aryl" as used herein means 5- and 6-membered single-ringaromatic radicals, and 10-membered double-ring aromatic radicals, whichmay include from zero to four heteroatoms, and within which includesfrom zero to three heteroatoms, and within which further includes fromzero to two heteroatoms, and within which further includes from zero toone heteroatom. Representative aryls include phenyl, thienyl, furanyl,pyridinyl, imidazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,(is)oxazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridinyl-N-oxide and thelike.

The phrase "aryl-substituted aryl" as used herein means an aryl group,as defined above, which has an aryl group, as defined above, or analkylaryl group, as defined above, attached thereto.

The abbreviation "Boc" as used herein means t-butyloxycarbonyl.

The abbreviation "Calc." as used herein means calculated.

The term "carbonyl" as used herein means a ##STR4## group.

The term "carboxy" as used herein means a ##STR5## group.

The term "composition" as used herein means a product which results fromthe combining of more than one element or ingredient.

The term "cyano" as used herein means a --CN group.

The term "cycloalkyl" as used herein means a nonaromatic cyclic ringradical having from one to ten carbon atoms, and within which includesfrom one to six carbon atoms, and further within which includes from oneto three carbon atoms, such as cyclohexane.

The abbreviation "DMAP" as used herein means 4-(dimethylamino)pyridine.

The abbreviation "DMF" as used herein means dimethylformamide.

The abbreviation "DR" as used herein means dose ratio.

The abbreviation "DSC" as used herein means Differential ScanningCalorimetry.

The phrase "EC₅₀ concentration" as used herein means that concentrationof a compound or drug which is necessary to elicit a 50% maximalbiological response and, thus, which is necessary to elicit a 50%reduction in the contractions of guinea pig ileum segments in aprostaglandin antagonism assay.

The phrase "ED₅₀ dose" as used herein means that dose of a compound ordrug which produced a biological effect, such as producing analgesia, in50% of the animals to which the compound or drug was administered.

The abbreviation "Et" as used herein means ethyl (--CH₂ CH₃).

The abbreviation "Et₂ " as used herein means ether.

The abbreviation "Et₂ O" as used herein means diethyl ether.

The abbreviation "EtOAc" as used herein means ethyl acetate.

The abbreviation "EtOH" as used herein means ethanol (CH₃ CH₂ OH).

The abbreviation "Et₂ N" as used herein means triethylamine.

The term "halo" or "halogen" as used herein means chlorine (Cl), bromine(Br), fluorine (F) and/or iodine (I).

The term "heteroatom" as used herein means an atom of any element otherthan carbon or hydrogen.

The abbreviation "¹ H NMR" as used herein means Proton Nuclear MagneticResonance.

The abbreviation "HPLC" as used herein means High Pressure LiquidChromatography.

The term "hydroxy" as used herein means the group --OH.

The term "intragastrically" and/or the abbreviation "i.g." as usedherein means that a compound or drug was administered into the stomach.

The abbreviation "i.p." as used herein means that a compound or drug wasadministered intraperitoneally.

The abbreviation "IR" as used herein means infrared, referring to aninfrared spectrum.

The abbreviation "LAH" as used herein means lithium aluminum hydride.

The abbreviation "Me" as used herein means methyl (--CH₃).

The abbreviation "MeOH" as used herein means methanol (CH₃ OH).

The abbreviation "mp" as used herein means melting point.

The abbreviation "MPLC" as used herein means Medium Pressure LiquidChromatography.

The term "nitro" as used herein means an --NO₂ group.

The abbreviation "n-BuLi" as used herein means n-butyl lithium.

The abbreviation "NMR" as used herein means Nuclear Magnetic Resonance.

The abbreviation "n-Pr" as used herein means n-propyl.

The phrases "parenteral administration" and "administered parenterally"as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrase "pharmaceutically acceptable" is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically-acceptable carrier" as used herein means apharmaceutically-acceptable material, composition or vehicle, as defineddirectly above, such as a liquid or solid filler, diluent, excipient,solvent or encapsulating material, involved in carrying or transportinga chemical compound or pharmaceutical agent from one organ, or portionof the body, to another organ, or portion of the body. Some examples ofmaterials which can serve as pharmaceutically-acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) excipients, such as cocoa butter and suppository waxes; (9)oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar; (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) Ringer's solution; ( 19) ethyl alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

The phrase "pharmaceutically-acceptable salts" as used herein refers tonon-toxic salts of the compounds of the present invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid, or which are prepared by reacting the free acid with asuitable base. Representative salts include the hydrochloride,hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, palmitate,stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, napsylate, clavulanate and thelike salts, and alkali metal salts, such as sodium and potassium, andalkaline earth salts, such as calcium and magnesium.

The abbreviation "p.o." as used herein means that a compound or drug wasadministered orally.

The phrase "protecting group" as used herein means substituents whichprotect the reactive functional group from undesirable chemicalreactions. Examples of such protecting groups include esters ofcarboxylic acids, ethers of alcohols and acetals and ketals of aldehydesand ketones.

The phrase "N-protecting group" or "N-protected" as used herein meansthose groups intended to protect the N-terminus of an amino acid orpeptide, to protect an amino group against undesirable reactions duringsynthetic procedures and includes, but is not limited to, sulfonyl,acetyl, pivaloyl, t-butyloxycarbonyl (Boc), carbonylbenzyloxy (Cbz),benzoyl and an L- or D-aminoacyl residue, which may itself beN-protected similarly.

The abbreviation "RaNi" as used herein means Raney nickel.

The abbreviation "s.c." as used herein means that a compound or drug wasadministered subcutaneously.

The term "sulfonyl" as used herein means an ##STR6## group.

The abbreviation "t-Bu" as used herein means tert-butyl.

The abbreviation "TEA" as used herein means triethylamine.

The phrase "therapeutically-effective amount" as used herein means anamount of a compound, material, or composition which is an effectivedose for eliminating or ameliorating pain in an animal, or for producingsome other desired therapeutic effect, at a reasonable benefit/riskratio applicable to any medical treatment.

The abbreviation "THF" as used herein means tetrahydrofuran.

The phrases "title compound," "title product" and "title material" asused herein mean that compound, product or material whose chemical nameis given, and/or whose structure is shown, in the particular example, orsubpart thereof, referred to. If no particular example, or subpartthereof, is referred to, it means that compound, product or materialwhose chemical name is given, and/or whose structure is shown, in theparticular example, or subpart thereof, in which it appears.

Description of Invention

In one aspect, the present invention provides compounds comprising astructure of Formula I, as described above, andpharmaceutically-acceptable salts, esters and amides thereof.

The compounds of the present invention comprise a class of substituteddibenzoxazepine and dibenzthiazepine compounds in which the 2-, 3-, 4-,5-, 6-, 7-, 8-, 9- and/or 10-position is substituted. Compounds withinthe present invention have been shown to exhibit activity asprostaglandin E₂ antagonists.

Specific compounds within the scope of the invention include, but arenot limited to, the compounds discussed in the examples presented below,as well as their pharmaceutically-acceptable salts, esters, and amides.

Contemplated equivalents of the compounds described in Formula I includecompounds which otherwise correspond thereto, and which have the samegeneral properties thereof, wherein one or more simple variations ofsubstituents are made which do not adversely affect the efficacy of thecompound.

Certain compounds of this invention may exist in geometric orstereoisomeric forms. The present invention contemplates all suchcompounds, including cis- and trans- geometric isomers, R- andS-enantiomers, diastereomers, d-isomers, l-isomers, the racemic mixturesthereof, and other mixtures thereof, as falling within the scope of theinvention. Additional asymmetric carbon atoms may be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

Certain compounds of the present invention may contain a basicfunctional group, such as amino, alkylamino or dialkylamino, and are,thus, capable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term "pharmaceutically-acceptablesalts" in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ during the final isolation andpurification of the compounds of the invention, or by separatelyreacting a purified compound of the invention in its free base form witha suitable organic or inorganic acid, and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, for example, S. M. Berge et al., "Pharmaceutical Salts," J. Pharm.Sci., 66 1-19 (977), which, as well as all other documents referred toherein, is incorporated herein by reference.)

In other cases, the compounds of the invention may contain one or moreacidic functional groups, such as carboxyl and the like, and, thus, arecapable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable bases. The term "pharmaceutically-acceptablesalts" in these instances refers to the relatively non-toxic, inorganicand organic base addition salts of compounds of the present invention.These salts can likewise be prepared in situ during the final isolationand purification of the compounds, or by separately reacting thepurified compound in its free acid form with a suitable base, such asthe hydroxide, carbonate or bicarbonate of a metal cation, with ammonia,or with a pharmaceutically-acceptable organic primary, secondary ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium, and aluminum saltsand the like. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine and the like. (See, forexample, S. M. Berge et al., "Pharmaceutical Salts," supra.)

In another aspect, the present invention providespharmaceutically-acceptable compositions which comprise atherapeutically-effective amount of one or more of the compounds ofFormula I, as described hereinabove, formulated together with one ormore pharmaceutically-acceptable carriers. The pharmaceuticalcompositions of the invention may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal or vaginal administration.

In yet a further aspect, the present invention provides a method foreliminating or ameliorating pain in an animal, or for producing someother therapeutic effect in an animal, such as for treatingProstaglandin-E₂ mediated diseases, as discussed in more detailhereinbelow, comprising administering a therapeutically-effective amountof a compound of Formula I, as described hereinabove, to the animal.

The preferred embodiments of this invention are the compounds describedin Examples 24, 34 and 58 below. The most preferred embodiment of theinvention is the compound described in Example 24 below.

Utility

Compounds within the present invention, and the pharmaceuticalcompositions comprising one or more of these compounds, are useful asanalgesic agents for the elimination or amelioration of pain in animals.

Compounds of the present invention exhibit activity as prostaglandin E₂antagonists (prostaglandin antagonists of the E₂ series). Thus, theywould be useful for the treatment of diseases in an animal which areresponsive to prostaglandin-E₂ antagonists.

In addition to treating pain, the compounds and compositions of thepresent invention would be useful in treating convulsions, ischemia andother central nervous system disorders, as well as osteoporosis,dysmenorrhea, asthma, enuresis, arrhythmia, urinary incontinence,gastric hypermotility, irritable bowel syndrome and diarrhea, by virtueof their activity as prostaglandin E₂ antagonists.

Methods of Preparation

In general, the compounds of the present invention may be prepared bythe methods illustrated in the following general reaction schemes, or bymodifications thereof, using readily available starting materials,reagents and conventional synthesis procedures. Unless otherwisespecified, the various substituents of the compounds are defined in thesame manner as they are defined above in Formula I in the "Summary ofInvention" section.

If a particular enantiomer of a compound of the present invention isdesired, it may be prepared by chiral synthesis, or by derivation with achiral auxiliary, where the resulting diastereomeric mixture isseparated and the auxiliary group cleaved to provide the pure desiredenantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

In General Reaction Scheme No. 1, the sodium salt of a substituted orunsubstituted (Y is hydrogen, halogen or hydroxy) 2-hydroxy or 2-thiolbenzaldehyde is generated by treatment with sodium hydride (NaH) indimethylformamide (DMF). This material is heated with a substituted orunsubstituted (Z is hydrogen or halogen) 2-dichloro nitrobenzene. Thenitro group of the condensate is reduced to an amino function withhydrogen using raney nickel as catalyst. Spontaneous cyclization of theamino group with the aldehyde occurs with a subsequent dehydration andfurther reduction to the dibenzoxazepine or dibenzthiazepine product. Bytreatment of this product with phosgene in toluene, the carbamoylchloride (A equals carbonyl) is produced. This material is condensedwith a cyclic secondary amine (B is nitrogen) in methylene chloridesolution. The reaction is carried out in the presence of an equivalentof triethyl amine to neutralize the HCl generated in the transformationand molecular sieves to remove any water in the system.

The cyclic secondary amine is a compound in which, when D is --CH, m andn may be the same or different, and may each be an integer independentlyof from 0 to 4, but not each being zero, and t is an integer of from 0to 1. When t is 1, q is 1, R is hydrogen or --CO₂ R¹ and R¹ is eitherhydrogen or alkyl. In either case, where t is 0 or 1, E is alkylene,carbonyl, alkyleneamino, or alkylenecarbonyl, p is an integer from 0 to1, and G is hydrogen, alkyl, cycloalkyl, alkoxy, aminoalkyl,aminocycloalkyl, aryl, alkylaryl or aryl-substituted aryl.

The cyclic secondary amine is also a compound in which, when D iscarbon, m or n may be the same or different, and may each be an integerindependently of from 0 to 4, but not each being zero. In this case, tis only 1, q is then 0, E is alkylene, carbonyl, alkyleneamino, oralkylenecarbonyl, p is an integer of from 0 to 1, and G is hydrogen,alkyl, cycloalkyl, alkoxy, aminoalkyl, aminocycloalkyl, aryl, alkylarylor aryl-substituted aryl.

The cyclic secondary amine is also a compound in which, when D isnitrogen, m may be an integer of from 2 to 4 and n may be an integer offrom 1 to 4. In this case, t is 0 or 1 and, when t is 1, q is 1 and R ishydrogen or --CO₂ R¹ The group R¹ is either hydrogen or alkyl and E isalkylene, carbonyl, alkyleneamino or alkylenecarbonyl, p is an integerof from 0 to 1 and G is hydrogen, alkyl, cycloalkyl, alkoxy, aminoalkyl,aminocycloalkyl, aryl, alkylaryl or aryl-substituted aryl.

If a basic atom is present in the molecule, the HCl salt is generated bytreatment of the product amine in diethyl ether or methanol with 6NHCl/dioxane. Either the free bases or HCl salts, in the case where X issulfur, may be oxidized to the sulfoxide by treatment with 30% H₂ O₂ inacetic acid at room temperature, and to the sulfone by treatment with30% H₂ O₂ in acetic acid at 50° C.

In General Reaction Scheme No. 2, an alternative and complementaryprocedure is used for obtaining compounds of this invention. Thus, inthis scheme, the carbamoyl chloride (A equals CO--Cl) of either tricycleas defined in the discussion for General Reaction Scheme No. 1 iscondensed with cyclic secondary amines where B and D are both nitrogen,m may be an integer of from 2 to 4 and n may be an integer of from 1 to4. In this case, t is 0 or 1 and, when t is 1, q is 1 and R is hydrogenor --CO₂ R¹. The group R¹ is alkyl, E is a carbonyl, p is 1 and G isalkoxy. The reaction is carried out in the presence of an equivalent oftriethyl amine to neutralize the HCl generated in the transformation andmolecular sieves to remove any water in the system. The alkoxy carbonylfunction is then removed either by treatment with HCl in dioxane or withsodium hydroxide and hydrazine in dioxane. The product of this reactionis then coupled to an acid function represented by HO--E--G where E is acarbonyl, p is 1 and G is alkyl, cycloalkyl, aryl, alkylaryl oraryl-substituted aryl. The coupling is achieved by reacting the abovereagents with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, 1-hydroxy benzotriazole hydrate, and triethyl amine indimethylformamide (DMF) solution.

If a basic nitrogen is present in the molecule, the HCl salt isgenerated by treatment of the product amine in diethyl ether with 6NHCl/dioxane. Either the free bases or HCl salts, in the case where X issulfur, may be oxidized to the sulfoxide by treatment with 30% H₂ O₂ inacetic acid at room temperature and to the sulfone by treatment with 30%H₂ O₂ in acetic acid at 50° C.

In General Reaction Scheme No. 3, an alternative and complementaryprocedure is used for obtaining compounds of this invention. Thus, inthis scheme, the cyclic secondary diamine (B and D are each nitrogen) isa compound where one of the amines is protected with a tert-butoxycarbonyl function (Boc), n and m are each integers of from 2 to 4, and tis 0. This material is coupled to an acid where E is a carbonyl, p is 1,and G is alkyl, cycloalkyl, aryl, alkylaryl or aryl-substituted aryl.The coupling is achieved by reacting the above reagents with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole hydrate, and triethyl amine, in DMF solution or withisobutylchloroformate and N-methylmorpholine in methylene chloridesolution. The cyclic secondary diamine is also coupled to an aldehydewhere E is a carbonyl and G is alkyl, cycloalkyl, aryl, alkylaryl oraryl-substituted aryl. This reaction is carried out in the presence ofsodium cyanoborohydride in methanol or hydrogen in methanol using Pd/Cas catalyst.

The Boc protecting group is removed from these products by treatmentwith 6N HCl/dioxane in acetic acid. The resulting HCl salt is thencondensed with the carbamoyl chloride (A equals CO--Cl) of eithertricycle as defined in the discussion for General Reaction Scheme No. 1.The reaction is carried out in methylene chloride in the presence of twoequivalents of triethyl amine to neutralize the HCl of the aminereactant and the HCl generated in the transformation and molecularsieves to remove any water in the system.

If a basic nitrogen is present in the molecule, the HCl salt isgenerated by treatment of the product amine in either diethyl ether ormethanol with 6N HCl/dioxane. Either the free bases or HCl salts, in thecase where X is sulfur, may be oxidized to the sulfoxide by treatmentwith 30% H₂ O₂ in acetic acid at room temperature, and to the sulfone bytreatment with 30% H₂ O₂ in acetic acid at 50° C.

In General Reaction Scheme No. 4, another alternative and complementaryprocedure is used for obtaining compounds of this invention. Thus, inthis scheme, either tricycle, as defined in the discussion of GeneralReaction Scheme No. 1, is reacted with a cyclic compound containing adisplaceable function J which is halogen or alkyl or aryl sulfonate.This cyclic compound is a material where D is carbon or nitrogen, m andn may be the same or different, and may each be an integer of from 0 to4, but not each being zero. In this case, t is 0, E is alkylene,carbonyl, alkyleneamino or alkylenecarbonyl, p is an integer of from 0to 1, and G is hydrogen, alkyl, cycloalkyl, alkoxy, aminoalkyl,aminocycloalkyl, aryl, alkylaryl or aryl-substituted aryl.

If a basic nitrogen is present in the molecule, the HCl salt isgenerated by treatment of the product amine in either diethyl ether ormethanol/water with 6N HCl/dioxane. Either the free bases or HCl salts,in the case where X is sulfur, may be oxidized to the sulfoxide bytreatment with 30% H₂ O₂ in acetic acid at room temperature, and to thesulfone by treatment with 30% H₂ O₂ in acetic acid at 50° C. ##STR7##

The conditions for carrying out the individual steps in each of thegeneral reaction schemes presented above are conventional, well-known,and capable of wide variation.

Other methods known in the art can also be used to synthesize thecompounds of the present invention.

Dosage and Mode of Administration

The compounds of the present invention, and the pharmaceuticalcompositions comprising one or more of these compounds in combinationwith a pharmaceutically-acceptable carrier, are useful in treating painin animals. A physician or veterinarian of ordinary skill in the art canreadily determine whether or not a patient is in pain.

The pharmaceutical compositions of the present invention, which willtypically comprise one or more of the compounds of Formula I as anactive ingredient in admixture with one or morepharmaceutically-acceptable carriers and, optionally, with one or moreother compounds, drugs or materials, are employed therapeutically and,thus, would generally be used under the guidance of a physician. Theappropriate dosage and form of administration of these compositions willbe suitably selected by methods which are consistent with conventionalpharmaceutical practices.

The pharmaceutical compositions of the present invention may bespecially formulated for oral administration in solid or liquid form,for parenteral injection, and/or for rectal or vaginal administration.They may be administered to humans and other animals for therapy by anysuitable route of administration, including orally, nasally, as by, forexample, a spray, rectally, intravaginally, parenterally,intracisternally and topically, as by powders, ointments or drops,including buccally and sublingually. While the preferred routes ofadministration are orally and parenterally, the most preferred mode ofadministration is orally.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the severity of the pain, theduration of the treatment, other drugs, compounds and/or materials usedin combination with the particular compound employed, the age, sex,weight, condition, general health and prior medical history of thepatient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required to alleviate or ameliorate a particular patient'spain. For example, the physician or veterinarian could start doses ofthe compound of the invention employed in the pharmaceutical compositionat levels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, dosage levels in therange of from about 0.001 mg to about 10 g, more preferably from about 1mg to about 1000 mg, of active compound per kilogram of body weight perday are administered to a mammalian patient. However, the total dailyusage of the compounds of Formula I, or the pharmaceutical compositionscomprising such compounds, will be determined by an attending physicianor veterinarian within the scope of sound medical judgement.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

The pharmaceutical compositions of the present invention comprise acompound of the present invention together with one or morepharmaceutically-acceptable carriers thereof and, optionally, with othertherapeutic agents. Each carrier must be "acceptable" in the sense ofbeing compatible with the other ingredients of the formulation and notinjurious to the patient.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfite, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate,alpha-tocopherol, and the like; and (3) metal chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient (compoundof Formula I) which can be combined with a carrier material to produce asingle dosage form will vary depending upon the host being treated, theparticular mode of administration and all of the other factors describedabove. The amount of active ingredient which can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound which is the lowest dose effective to produce atherapeutic effect. Generally, out of one hundred percent, this amountwill range from about 1 percent to about ninety-nine percent of activeingredient, preferably from about 5 percent to about 70 percent, mostpreferably from about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, with one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient (compound of Formula I) is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds; (7) wetting agents, such as, for example, cetylalcohol and glycerol monostearate; (8) absorbents, such as kaolin andbentonite clay; (9) lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and (10) coloring agents. In the case of capsules,tablets and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient (compound of Formula I as described above), the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn, germ, oliveand sesame oils), glycerol, tetrahydrofuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a Pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the invention to the body. Such dosage formscan be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a Parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of drug to polymer, and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissue.

The injectable materials can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or in other sterile injectable mediumsjust prior to use.

The formulations may be presented in unit-dose or multi-dose sealedcontainers, for example, ampoules and vials, and may be stored in alyophilized condition requiring only the addition of the sterile liquidcarrier, for example water for injections, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the type described above.

The pharmaceutical compositions of the present invention may also beused in the form of veterinary formulations, including those adapted forthe following: (1) oral administration, for example, drenches (aqueousor non-aqueous solutions or suspensions), tablets, boluses, powders,granules or pellets for admixture with feed stuffs, pastes forapplication to the tongue; (2) parenteral administration, for example,by subcutaneous, intramuscular or intravenous injection as, for example,a sterile solution or suspension or, when appropriate, by intramammaryinjection where a suspension or solution is introduced into the udder ofthe animal via its teat; (3) topical application, for example, as acream, ointment or spray applied to the skin; or (4) intravaginally, forexample, as a pessary, cream or foam.

While the various aspects of the present invention are described hereinwith some particularity, those of skill in the art will recognizenumerous modifications and variations which remain within the spirit ofthe invention. These modifications and variations are within the scopeof the invention as described and claimed herein.

EXAMPLES

The following examples describe and illustrate the methods for thepreparation of the compounds of the present invention, as well as otheraspects of the present invention, and the results achieved thereby, infurther detail. Both an explanation of, and the actual procedures for,the various aspects of the present invention are described whereappropriate. These examples are intended to be merely illustrative ofthe present invention, and not limiting thereof in either scope orspirit. Those of skill in the art will readily understand that knownvariations of the conditions and processes of the preparative proceduresdescribed in these examples can be used to prepare the compounds of thepresent invention, and the pharmaceutical compositions comprising suchcompounds.

In the examples, all parts are by weight unless otherwise indicated.

All equipment employed in the examples is commercially available. Unlessotherwise indicated, all starting materials employed in the examples arecommercially available. Sources for these materials include SigmaChemical Co. (St. Louis, Mo.), Aldrich Chemical Co. (Milwaukee, Wis.),Lancaster Synthesis (Windham, N.H.), Fisher Scientific (Pittsburgh,Pa.), Boehringer Mannheim Biochemicals (Indianapolis, Ind.), FlukaChemical Corp. (Ronkonkoma, N.Y.), Johnson Matthey Co. (West Deptford,N.J.), Eastman Kodak Co. (Rochester, N.Y.), Emkay Chemical Co.(Elizabeth, N.J.), Maybridge Chemical (Columbia, S.C.) and ChemicalDynamics Corp. (South Plainfield, N.J.). Most of the starting materialswere obtained from Aldrich Chemical Co. (Milwaukee, Wis.).

All patents and publications referred to in the examples, and throughoutthe specification, are hereby incorporated herein by reference, withoutadmission that such is prior art.

Example 1

8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine ##STR8##

The synthesis of the title compound is described in U.S. Pat. No.3,534,019, which is incorporated herein by reference.

Briefly, 200 parts of 2,5-dichloro-nitrobenzene were heated to 160° C.and stirred, and 160 parts of the potassium salt of salicylaldehyde wasadded over a period of 30 minutes. After the addition was complete, anexothermic reaction took place, and the temperature rose to about 195°C. Heating was discontinued until the reaction subsided, and the mixturewas heated for 1 hour at 150° C. The mixture was cooled, ice and waterwere added, and it was extracted with ether (Et₂ O). The ether layer wasfiltered to remove insoluble material, and the resultant solution wasdried over sodium sulfate. The ether solvent was evaporated, and theresidual oil was recrystallized from a mixture of hexane and benzene togive 2-(2-nitro-4-chlorophenoxy)benzaldehyde melting at about 100°-101°C.

A solution of 55 parts of the ether obtained in the preceding paragraphin 800 parts of ethanol was hydrogenated over Raney nickel catalyst atroom temperature and atmospheric pressure. When hydrogen uptake ceased,the catalyst was removed by filtration, and the ethanol solvent wasevaporated. The residue was dissolved in 500 parts by volume of hexane,filtered, and cooled. There was obtained yellowish-white crystals whichwere separated by filtration to give the title compound melting at about94°-95° C.

Example 2

8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carbonyl chloride (2)##STR9##

The title compound was also synthesized in the manner described in U.S.Pat. No. 3,534,019.

13 parts of phosgene in 45 parts of toluene was stirred for 2 hours at5°-10° C., and then 70 parts of ether was added. This was followed bythe addition of a solution of 18.9 parts of the title compound ofExample 1 and 7.2 parts of triethylamine in 140 parts of ether. Afterthe addition was complete, the mixture was stirred for 2 hours, and thenwas filtered. The solvent was then evaporated from the filtrate. Theresulting residue was then dissolved in 200 parts by volume of hothexane, and this mixture was then filtered and cooled.

Example 3

1-[{8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-N,N-bis(2-hydroxyethyl)-4-piperidinecarboxamide##STR10##

A sample of methyl isonicotinate (137 g, 1.0 mole) was heated neat withdiethanolamine (126 g, 1 mole). After cooling to room temperature, thecrystallized product was filtered, washed with isopropanol, washed withEt₂ O, and dried in vacuo to yield 179 g (84%) of the desired diethanolisonicotinamide.

A 45.0 g sample (0.22 mole) of the diethanol isonicotinamide dissolvedin 500 mL of dioxane was placed in a 2 L Parr bomb along with 4.5 g ofRuO₂. The bomb was heated to 100° C. and maintained at this temperaturefor 30 minutes under a hydrogen pressure of 1000 psi. The bomb wascooled to room temperature and another 500 mL of dioxane were added. Thereduction was run again at 100° C. for 30 minutes under a hydrogenpressure of 1000 psi. After cooling the reaction to room temperature andremoval of the catalyst by filtration, the dioxane was decanted from thelight tan product oil, N,N-bis(2-hydroxyethyl)-4-piperidinecarboxamide(36.7 g).

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined withN,N-bis(2-hydroxyethyl)-4-piperidinecarboxamide (0.83 g, 4.1 mmol),triethylamine (0.41 g, 4.1 mmol), molecular sieves #3A (5 g), 60 mL ofmethylene chloride (CH₂ Cl₂), and 8 mL dimethylformamide (DMF). Afterstirring this mixture for 24 hours at room temperature (rt) and under anitrogen (N₂) atmosphere, it was filtered and the solid was washedliberally with ethyl acetate (EtOAc) and 0.5N potassium bisulfate(KHSO₄). The organic layer was separated from the filtrate, washed with0.5N KHSO₄ and brine. After removing all solvent under reduced pressure,the residue oil (1.5 g) was chromatographed to yield 0.5 g of the titlematerial.

Calculated for C₂₄ H₂₈ N₃ O₅ Cl+0.25 H₂ O+0.1 CH₂ Cl₂ (MW=486.95): C,59.44; H, 5.94; N, 8.63; Cl, 8.74. Found: C, 59.78; H, 5.92; N, 8.49;Cl, 8.68.

Example 4

8-chloro-10,11-dihydro-10-[(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)carbonyl]dibenz[b,f][1,4]oxazepine##STR11##

Methyl picolinate (300 g, 2.1 mole) and 3 g of its HCl salt weredissolved in 2 L of ethanol. To this solution heated to reflux withstirring, under N₂, was added a 2B ethanol solution (850 mL) of ethyleneimine (120 g, 2.8 mole) over a 3 hour period. Following completion ofaddition, the reaction was refluxed overnight. The solvent was distilledoff under vacuum and the residue was treated with acetone. Afterconcentrating the solution, 88 g ofhexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one crystallized from thesolution.

A sample of this lactam (168 g, 1.1 mole) dissolved in 2 L of dioxanewas added to a refluxing solution of LiAlH₄ (40.0 g, 1.05 mole) in 1 Lof dioxane over 2 hours. After refluxing the reaction overnight, it wascooled to room temperature and quenched with a mixture of 20% NaOH indioxane. The resulting mixture was filtered through supercell andstripped of all solvent under reduced pressure. The residue wasdistilled to give 169 g of the desiredoctahydro-2H-pyrido[1,2-a]pyrazine.

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined withoctahydro-2H-pyrido[1,2-a]pyrazine (0.49 g, 3.5 mmol), triethylamine(0.41 g, 4.1 mmol), molecular sieve #3A (5 g), 60 mL of CH₂ Cl₂, and 8mL DMF. After stirring this mixture for 24 hours at room temperature andunder a N₂ atmosphere, it was filtered and the solid was washedliberally with EtOAc and 1N potassium carbonate (K₂ CO₃). The organiclayer was separated from the filtrate, washed with 1N K₂ CO₃ and brine.After removing all solvent under reduced pressure, the residue oil/glass(1.7 g) was chromatographed to yield 1.14 g of the title material.

Calculated for C₂₂ H₂₄ N₃ O₂ Cl+0.125 H₂ O+0.05 CH₂ Cl₂ (MW=404.41): C,65.49; H, 6.07; N, 10.39; Cl, 9.64. Found: C, 65.49; H, 5.92; N, 10.29;Cl, 9.77.

Example 5

8-chloro-10,11-dihydro-10-[(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)carbonyl]dibenz[b,f][1,4]oxazepinehydrochloride ##STR12##

The title compound of Example 4 (1.0 g, 2.5 mmol) dissolved in 75 mL ofEt₂ O was treated dropwise with 6.9 N hydrochloric acid (HCl) in dioxaneuntil no further precipitation of solid was noted on the addition offurther drops of HCl. The white solid was filtered, washed with Et₂ Oand dried in vacuo. A 1.0 g sample of the white solid powder titleproduct was obtained.

Calculated for C₂₂ H₂₄ N₃ O₂ Cl+HCl+0.25 H₂ O (MW=438.87): C, 60.21; H,5.86; N, 9.57; Cl, 16.16. Found: C, 60.01; H, 5.81; N, 9.41; Cl, 15.01.

Example 6

8-chloro-10,11-dihydro-10-[[4-(phenylmethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR13##

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined withN-benzylpiperazine (0.60 g, 3.4 mmol) and the reaction was carried outby the method of Example 4. Following chromatographic separation, 1.4 gof the white solid title product was obtained.

Calculated for C₂₅ H₂₄ N₃ O₂ Cl+0.05 CH₂ Cl₂ (MW=438.19): C, 68.66; H,5.54; N, 9.59; Cl, 8.90. Found: C, 68.60; H, 5.57; N, 9.49; Cl, 9.02.

Example 7

8-chloro-10,11-dihydro-10-[[4-(phenylmethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR14##

The title material was synthesized from the title material of Example 6(1.30 g, 3.0 mmol) by the method of Example 5. A 1.32 g sample of thewhite solid title compound was obtained.

Calculated for C₂₅ H₂₄ N₃ O₂ Cl+HCl+0.25 H₂ O (MW=474.90): C, 63.23; H,5.41; N, 8.85; Cl, 14.93. Found: C, 63.25; H, 5.29; N, 8.75; Cl, 14.24.

Example 8

10-[(4-butyl-1-piperazinyl)carbonyl]-8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine##STR15##

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined withn-butyl-N-piperazine (0.48 g, 3.4 mmol) and the reaction was carried outby the method of Example 4. Following chromatographic separation, 1.22 gof the clear viscous oil title product was obtained.

Calculated for C₂₂ H₂₆ N₃ O₂ Cl+0.05 CH₂ Cl₂ (MW=404.17): C, 65.53; H,6.51; N, 10.40; Cl, 9.65. Found: C, 65.82; H, 6.67; N, 10.40; Cl, 11.07.

Example 9

10-[(4-butyl-1-piperazinyl)carbonyl]-8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine,monohydrochloride ##STR16##

The title material was synthesized from the title material of Example 8(1.12 g, 2.8 mmol) by the method of Example 5. A 1.11 g sample of thewhite solid title compound was obtained.

Calculated for C₂₂ H₂₆ N₃ O₂ Cl+HCl+0.25 H₂ O (MW=440.89): C, 59.93; H,6.29; N, 9.58; Cl, 16.08. Found: C, 60.00; H, 6.18; N, 9.48; Cl, 15.47.

Example 10

8-chloro-10,11-dihydro-10-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR17##

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with1-(2-pyridyl)piperazine (0.56 g, 3.4 mmol) and the reaction was carriedout by the method of Example 4. Following chromatographic purification,1.16 g of the title product was obtained.

Calculated for C₂₃ H₂₁ N₄ O₂ Cl+0.075 CH₂ Cl₂ +0.125 H₂ O (MW=429.52):C, 64.53; H, 5.02; N, 13.04; Cl, 9.65. Found: C, 64.28; H, 5.05; N,12.87; Cl, 9.43.

Example 11

8-chloro-10,11-dihydro-10-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR18##

The title compound was synthesized from the title material of Example 10(1.12 g, 2.8 mmol) by the method of Example 5. A 1.32 g sample of thewhite solid title compound was obtained.

Calculated for C₂₂ H₂₆ N₃ O₂ Cl+HCl+0.25 H₂ O (MW=440.89): C, 59.93; H,6.29; N, 9.58; Cl, 16.08. Found: C, 60.00; H, 6.18; N, 9.48; Cl, 15.

Example 12

10-([1,4'-bipiperidin]-1'-ylcarbonyl)-8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine##STR19##

The title compound of Example 2 (0.6 g, 2.0 mmol) was combined with1,4'-bipiperidine (0.38 g, 2.2 mmol) and the reaction was carried out bythe method of Example 4. Following chromatographic purification, 0.74 gof the title product was obtained as a white solid.

Example 13

10-([1,4'-bipiperidin]-1'-ylcarbonyl)-8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine,hydrochloride ##STR20##

The title material was synthesized from the title material of Example 12(0.70 g, 1.6 mmol) by the method of Example 5. A 0.50 g sample of thewhite solid title product was obtained.

Calculated for C₂₄ H₂₈ N₃ O₂ Cl+0.9 HCl+0.5 H₂ O (MW=467.78): C, 61.62;H, 6.44; N, 8.98; Cl, 14.40. Found: C, 61.65; H, 6.30; N, 8.94; Cl,14.61.

Example 14

8-chloro-10-[(4-decyl-1-piperazinyl)carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine##STR21##

Ethyl 1-piperazinecarboxylate (77.3 g, 0.28 mole), 1-decanolmethanesulfonate (77.3 g, 0.28 mole) from the condensation of 1-decanolwith methane sulfonyl chloride, K₂ CO₃ (39.0 g, 0.28 mole), and 500 mLof EtOH were combined and refluxed for 2 days under N₂. After cooling toroom temperature, the reaction was partitioned between water and Et₂ O.The organic layer was separated, washed 3 times with water, dried overNa₂ SO₄ and stripped of all solvent under reduced pressure to yield thecrude product oil. Chromatographic purification of the crude oil gave53.4 g of ethyl 4-decyl-1-piperazinecarboxylate.

Ethyl 4-decyl-1-piperazinecarboxylate (53.4 g, 0.18 mole) in 300 mL ofconcentrated HCl was refluxed for 2 days under N₂. After all of thesolvent was removed under reduced pressure and the residue was suspendedin ethanol, the product 1-decylpiperazine hydrochloride (20.2 g) wasfiltered off and dried. This material was converted to its free base,1-decylpiperazine, by treatment with NaOH.

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with1-decylpiperazine (0.77 g, 3.4 mmol) and the reaction was carried out bythe method of Example 4. Following chromatographic purification, 1.08 gof the title product was obtained.

Example 15

8-chloro-10-[(4-decyl-1-piperazinyl)carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine,monohydrochloride ##STR22##

The title compound was synthesized from the title material of Example 14(0.91 g, 1.9 mmol) by the method of Example 5. A 0.87 g sample of thewhite solid title product was obtained.

Calculated for C₂₈ H₃₈ N₃ O₂ Cl+HCl+0.5 H₂ O (MW=520.54): C, 64.61; H,7.55; N, 8.07; Cl, 13.62. Found: C, 64.41; H, 7.53; N, 8.03; Cl, 13.36.

Example 16

8-chloro-10,11-dihydro-10-[(4-propyl-1-piperazinyl)carbonyl]dibenz[b,f][1,4]oxazepine##STR23##

By the methods of Example 14, ethyl 1-piperazinecarboxylate was reactedwith the methanesulfonate of n-propanol and the product, ethyl4-propyl-1-piperazinecarboxylate, was converted to 1-propylpiperazine.

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with1-propylpiperazine (0.44 g, 3.4 mmol) and the reaction was carried outby the method of Example 4. Following chromatographic purification, 1.16g of the title product was obtained as a white solid.

Example 17

8-chloro-10,11-dihydro-10-[(4-propyl-1-piperazinyl)carbonyl]dibenz[b,f][1,4]oxazepine,hydrochloride ##STR24##

The title compound was synthesized from the title material of Example 16(1.11 g, 2.9 mmol) by dissolving it in 28 mL of 2N HCl in methanol(MeOH). After stirring this solution for 30 minutes, all solvent wasremoved under reduced pressure. The resulting residue was washed withEt₂ O, dissolved in water, treated with activated charcoal, filtered andlyophilized. An 0.80 g sample of the pale green solid title product wasobtained.

Calculated for C₂₁ H₂₄ N₃ O₂ Cl+1.1 HCl+0.75 H₂ O (MW=439.51): C, 57.39;H, 6.10; N, 9.56; Cl, 16.94. Found: C, 57.69; H, 5,83; N, 9.58; Cl,17.26.

Example 18

8-chloro-10-[(4-ethyl-1-piperazinyl)carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine##STR25##

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with4-ethylpiperazine (0.43 g, 3.7 mmol) and the reaction was carried out bythe method of Example 4. Following chromatographic purification, 1.10 gof the title product was obtained as a pale yellow solid.

Example 19

8-chloro-10-[(4-ethyl-1-piperazinyl)carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine,hydrochloride ##STR26##

The title compound was synthesized from the title material of Example 18(0.99 g, 2.7 mmol) by the method of Example 17. An 0.93 g sample of thepale yellow solid title product was obtained.

Calculated for C₂₀ H₂₂ N₃ O₂ Cl+1.1 HCl+0.5 H₂ O (MW=420.98): C, 57.06;H, 5.77; N, 9.98; Cl, 17.69. Found: C, 57.11; H, 5,58; N, 10.03; Cl,17.79.

Example 20

1,1-dimethylethyl4-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-1-piperazinecarboxylate##STR27##

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with1,1-dimethylethyl 1-piperazinecarboxylate (0.44 g, 3.4 mmol) and thereaction was carried out by the method of Example 3. Followingchromatographic purification, 1.16 g of the title product was obtainedas a white solid.

Calculated for C₂₃ H₂₂₆ N₃ O₄ Cl+0.1 CH₂ Cl₂ (MW=452.42): C, 61.33; H,5.84; N, 9.40; Cl, 9.40. Found: C, 61.26; H, 5,90; N, 9.15; Cl, 9.09.

Example 21

8-chloro-10,11-dihydro-10-[[4-(1-methylethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR28##

Ethyl 1-piperazinecarboxylate (60.0 g, 0.3 mole), 2-bromopropane (73.8g, 0.6 mole), K₂ CO₃ (82.8 g, 0.6 mole), and 600 mL of EtOH werecombined and refluxed for overnight. After cooling to room temperature,all solvent was removed under reduced pressure. The residue wasdissolved in 200 mL of water and extracted with 2×250 mL of Et₂ O. Theorganic layer was separated, dried, and the ethyl4-(1-methylethyl)-1-piperazinecarboxylate product was precipitated asits HCl salt by treatment of the Et₂ O layer with HCl/isopropanol. Theproduct HCl salt was filtered, washed with Et₂ O, and dried (76 g).

After the preceding material (76 g), dissolved in 500 mL of concentratedHCl was refluxed overnight, all solvent was removed under reducedpressure. The residue product oil was treated with EtOH. The crystalline1-(1-methylethyl)piperazine dihydrochloride salt was filtered, washedwith Et₂ O, and dried.

This material was converted to its free base by treatment with 50%aqueous NaOH and extraction with Et₂ O. After drying the organic layer,all solvent was stripped and the residue was distilled at atmosphericpressure to give 22.1 g of 1-(1-methylethyl)piperazine (b.p.=168°-170°C.).

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with1-(1-methylethyl)piperazine (0.48 g, 3.7 mmol) and the reaction wascarried out by the method of Example 4. Following chromatographicpurification, 1.17 g of the title product was obtained as a white solid.

Example 22

8-chloro-10,11-dihydro-10-[[4-(1-methylethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine,hydrochloride ##STR29##

The title compound was synthesized from the title material of Example 21(0.99 g, 2.7 mmol) by the method of Example 17. A 0.93 g sample of thepale yellow solid title product was obtained.

Calculated for C₂₁ H₂₄ N₃ O₂ Cl+1.1 HCl+0.3 H₂ O (MW=431.40): C, 58.47;H, 6.00; N, 9.74. Found: C, 58.52; H, 6.06; N, 9.78.

Example 23

8-chloro-10,11-dihydro-10-[(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)carbonyl]dibenz[b,f][1,4]oxazepine##STR30##

A mixture of the product of Example 96 (37.0 g, 0.21 mole), n-propyltosylate (68.1 g, 0.31 mole), Na₂ CO₃ (16.8 g, 0.16 mole), and 160 mL ofEtOH were refluxed for 14 hours under N₂. After cooling the reaction, itwas filtered and all solvent was removed from the filtrate under reducedpressure. The residue was mixed with 300 mL of water and extracted with2×200 mL of Et₂ O. The product HCl salt was precipitated and convertedto hexahydro-1-propyl-1H-1,4-diazacycloheptane by the methods of Example21.

The title compound of Example 2 (1.0 g, 3.4 mmol) was combined withhexahydro-1-propyl-1H-1,4-diazacycloheptane (0.53 g, 3.7 mmol) and thereaction was carried out by the method of Example 4. Followingchromatographic purification, 1.20 g of the title product was obtainedas a pale yellow oil.

Example 24

8-chloro-10,11-dihydro-10-[(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR31##

The title compound was synthesized from the title material of Example 23(0.99 g, 2.7 mmol) by the method of Example 17. A 1.13 g sample of thesolid title product was obtained.

Calculated for C₂₂ H₂₆ N₃ O₂ Cl+1 HCl+0.4 H₂ O (MW=443.59): C, 59.57; H,6.32; N, 9.47; Cl, 15.98. Found: C, 59.48; H, 6.32; N, 9.45; Cl, 16.14.

Example 25

8-chloro-10,11-dihydro-10-(1-piperazinylcarbonyl)dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR32##

The title compound of Example 20 (5.0 g, 11.1 mmol) was dissolved in 40mL of acetic acid (HOAc). This homogeneous solution was then treatedwith 16 mL of 6.9N HCl dissolved in dioxane. After stirring this mixturefor 1 hour, all solvent was removed under reduced pressure. The residuewas dissolved in MeOH, stripped of all solvent, triturated with Et₂ O,filtered, washed with Et₂ O and dried in vacuo to provide 3.90 g of thewhite solid title salt.

Calculated for C₁₈ H₁₈ N₃ O₂ Cl+1 HCl+1.0 H₂ O+0.025 Et₂ O (MW=416.82):C, 54.75; H, 5.68; N, 10.08; Cl, 17.01. Found: C, 54.57; H, 5.35; N,10.01; Cl, 16.85.

Example 26

1,1-dimethylethyl 4-(4-pyridinylcarbonyl)-1-piperazinecarboxylate##STR33##

A sample of 4-pyridinecarboxylic acid (1.32 g, 10.7 mmol) was dissolvedin 50 mL of CH₂ Cl₂. To this solution under N₂ was addedN-methylmorpholine (1.21 mL, 11.0 mmol) before it was cooled to -78° C.and isobutylchloroformate (1.39 mL, 10.7 mmol) was added. The reactionwas allowed to warm to 0° C. and stirred at this temperature for 30minutes before it was cooled again to -78° C. and t-butyloxycarbonylpiperazine (2.0 g, 10.7 mmol) was added. The mixture was allowed to warmto room temperature and stirred for 18 hours. All solvent was removedunder reduced pressure to give a residue that was dissolved in EtOAc,washed with saturated NaHCO₃ and brine, and dried (Na₂ SO₄). After allsolvent was removed in vacuo, the residue was chromatographed togenerate 1.3 g of the title compound.

Example 27

1-(4-pyridinylcarbonyl)piperazine ##STR34##

The title material was synthesized from the title product of Example 26(1.3 g, 4.46 mmol) by the method described in Example 25, except thatthe title free base was generated by treatment of its HCl salt with 0.5NK₂ CO₃ in CH₂ Cl₂. The CH₂ Cl₂ solution was dried over Na₂ SO₄ and allsolvent removed under reduced pressure to provide 333 mg of the titlefree base. This material was used without further purification.

Example 28

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-(4-pyridinylcarbonyl)piperazine##STR35##

The title compound of Example 2 (0.51 g, 1.7 mmol) was reacted with thetitle product of Example 27 (0.33 g, 1.7 mmol) by the method of Example4. Following chromatographic purification, 0.16 g of the title productwas obtained.

Example 29

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-(4-pyridinylcarbonyl)piperazine,monohydrochloride ##STR36##

The title product of Example 28 was dissolved in 10 mL of MeOH. Excess6.9N HCl dioxane was added to the solution. After stirring this solutionfor 30 minutes, all solvent was removed under reduced pressure. Theresidue was dissolved in water/MeOH and lyophilized to produce 0.11 g ofthe title product as a granular white solid.

Calculated for C₂₄ H₂₁ N₄ O₃ Cl+1 HCl+0.8 H₂ O (MW=499.78): C, 57.68; H,4.76; N, 11.21; Cl, 14.19. Found: C, 57.49; H, 4.36; N, 10.93; Cl,13.91.

Example 30

1,1-dimethylethyl4-[1-oxo-3-(3-pyridinyl)propyl]-1-piperazinecarboxylate ##STR37##

A sample of 3-pyridinepropanoic acid (0.1 g, 0.7 mmol) was reacted witht-butyloxycarbonyl piperazine (0.19 g, 1.0 mmol) by the method ofExample 26 to produce 95 mg of the white solid title compound afterchromatography.

Example 31

1-[3-(3-pyridinyl)-1-oxopropyl]piperazine ##STR38##

The title product of Example 30 (95.0 mg, 0.30 mmol) was dissolved in 6mL of HOAc. To this solution was added 0.5 mL of 6N HCl in dioxane.After stirring this solution for 25 minutes, all solvent was removedunder reduced pressure to give 76 mg of the title product.

Example 32

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-[(1-oxo-3(3-pyridinyl)propyl]piperazine##STR39##

The title compound of Example 2 (0.51 g, 1.7 mmol) was reacted with thetitle product of Example 31 (0,076 g, 0.30 mmol) by the method ofExample 4, except that an additional 1.7 mmol of Et₃ N was used toneutralize the HCl salt of the title compound of Example 4. Followingchromatographic purification, 0.11 g of the title product was obtained.

Example 33

1-[(8-chlorodibenz[b,f][1.4]oxazepin-10(11H)-yl)carbonyl]-4-[1-oxo-3(3-pyridinyl)propyl]-piperazine,monohydrochloride ##STR40##

The title product of Example 32 (0.1 g, 0.21 mmol) was converted to thetitle compound by the method of Example 29. A 96 mg sample of this whitesolid salt was obtained.

Calculated for C₂₆ H₂₅ N₄ O₃ Cl+1 HCl+1.25 H₂ O (MW=535.94): C, 58.27;H, 5.36; N, 10.45; Cl, 13.23. Found: C, 58.12; H, 4.85; N, 10.34; Cl,13.27.

Example 34

8-chloro-10,11-dihydro-10-[[4-(1-pyrrolidinyl)-1-pieperidinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR41##

The title compound of Example 2 (1.0 g, 3.4 mmol) was reacted with4-(1-pyrrolidinyl)piperidine (0.77 g, 3.4 mmol) and the reaction wascarried out by the method of Example 4. Following chromatographicpurification, 0.91 g of the title product was obtained.

Example 35

8-chloro-10,11-dihydro-10-[[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl]dibenz[b,f][1,4]oxazepine,hydrochloride ##STR42##

The title product of Example 34 (0.90 g, 2.17 mmol) was converted to thetitle compound by the method of Example 29. A 0.55 g sample of thistitle white solid salt product was obtained.

Calculated for C₂₃ H₂₆ N₃ O₂ Cl+1.1 HCl+1 H₂ O (MW=470.05): C, 58.77; H,6.24; N, 8.94; Cl, 15.84. Found: C, 58.74; H, 5.53; N, 8.87; Cl, 15.56.

Example 36

1,1-dimethylethyl 4-(2-furanylcarbonyl)-1-piperazinecarboxylate##STR43##

t-Butyloxycarbonyl piperazine (2.0 g, 10.7 mmol) was reacted withfurancarbonyl chloride (1.40 g, 10.7 mmol) by the method of Example 4.Following chromatography, a 2.25 g sample of the title compound wasobtained.

Example 37

1-(2-furanylcarbonyl)piperazine hydrochloride ##STR44##

The title compound of Example 36 (2.25 g, 14.4 mmol) was converted tothe title product by the method of Example 31. A 1.4 g sample of thismaterial was obtained.

Calculated for C₉ H₁₂ N₂ O₂ Cl+1 HCl (MW=216.67): C, 49.89; H, 6.05; N,12.93; Cl, 16.36. Found: C, 49.79; H, 6.11; N, 12.82; Cl, 16.24.

Example 38

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-(2-furanylcarbonyl)piperazine##STR45##

The title compound of Example 2 (1.0 g, 3.4 mmol) was reacted with thetitle compound of Example 37 (0.76 g, 3.5 mmol), and the reaction wascarried out by the method of Example 4 with the modification of Example32. Following chromatographic purification, 1.10 g of the title productwas obtained as a white solid.

Calculated for C₂₃ H₂₀ N₃ O₄ Cl+0.375 H₂ O+0.1 CH₂ Cl₂ (MW=453.13): C,49.89; H, 6.05; N, 12.93; Cl, 16.36. Found: C, 49.79; H, 6.11; N, 12.82;Cl, 16.24.

Example 39 COMPOUND A

8-chloro-10,11-dihydro-10-[[4-(2-phenylethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR46##

COMPOUND B

10,11-dihydro-10-[[4-(2-phenylethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR47##

The title compound of Example 25 (1.0 g, 2.6 mmol), phenylacetaldehyde(0.40 g, 3.3 mmol), triethylamine (0.32 g, 3.2 mmol), 40 mL of EtOHtriethylamine, and 5% Palladium on carbon were combined in a standardParr hydrogenation shaker. This mixture was shaken under a hydrogen (H₂)atmosphere of 5 psi at room temperature for 9 hours. An uptake in H₂ of9.03 psi was observed. The reaction mixture was filtered and thefiltrate was stripped of solvent under reduced pressure before it wasdissolved in EtOAc (500 mL). This solution was washed with 1×75 mL of0.5N K₂ CO₃ and 2×75 mL of brine before it was dried (Na₂ SO₄) and allsolvent removed in vacuo. The residue was chromatographed to yield twowhite solid products; title COMPOUND A (0.75 g) and title COMPOUND B(0.15 g). COMPOUND A has a greater Rf than COMPOUND B when a thin layerchromatograph (TLC) on silica gel plates eluting with solvent system of40% EtOAC/hexane containing 0.05% NH₄ OH is performed.

COMPOUND A:

Calculated for C₂₆ H₂₆ N₃ O₂ Cl (MW=447.96): C, 69.71; H, 5.85; N, 9.38;Cl, 7.91. Found: C, 69.71 H, 5.74; N, 9.36; Cl, 7.75.

COMPOUND B:

Calculated for C₂₆ H₂₇ N₃ O₂ +0.5 H₂ O (MW=422.53): C, 73.91; H, 6.68;N, 9.95. Found: C, 74.08; H, 6.56; N, 9.89.

Example 40

8-chloro-10,11-dihydro-10-[[4-(2-phenylethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR48##

The title compound was synthesized from a title material of Example 39(COMPOUND A) (0.60 g, 1.3 mmol) by the method of Example 5. A 0.64 gsample of the white solid title compound was obtained.

Calculated for C₂₆ H₂₆ N₃ O₂ Cl+HCl (MW=497.94): C, 62.72; H, 5.77; N,8.44; Cl, 14.24. Found: C, 62.69 H, 5.55; N, 8.51; Cl, 13.57.

Example 41

10,11-dihydro-10-[[4-(2-phenylethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR49##

The title compound was synthesized from a title material of Example 39(COMPOUND B) (0.10 g, 0.2 mmol) by the method of Example 5. A 0.07 gsample of the white solid title compound was obtained.

Calculated for C₂₂ H₂₇ N₃ O₂ +HCl+0.25 H₂ O (MW=454.49): C, 68.71; H,6.32; N, 9.25; Cl, 7.80. Found: C, 68.71; H, 6.18; N, 9.48; Cl, 15.47.

Example 42

8-chloro-10,11-dihydro-10-[(4-phenyl-1-piperazinyl)carbonyl]dibenz[b,f][1,4]oxazepine,hydrochloride ##STR50##

The title compound of Example 2 (1.25 g, 4.25 mmol) was combined withN-phenylpiperazine (0.73 g, 4.5 mmol) and the reaction was carried outby the method of Example 4. Following chromatographic separation, 1.7 gof the white solid title product was obtained.

Calculated for C₂₄ H₂₂ N₃ O₂ Cl+0.01 CH₂ Cl₂ (MW=428.41): C, 67.57; H,5.22; N, 9.81; Cl, 9.83. Found: C, 67.47; H, 5.30; N, 9.75; Cl, 9.59.

Example 43

8-chloro-10,11-dihydro-10-[(4-phenyl-1-piperazinyl)carbonyl]dibenz[b,f][1,4]oxazepine,hydrochloride ##STR51##

The title material was synthesized from the title material of Example 42(1.55 g 3.0 mmol) by the method of Example 5. A 1.67 g sample of thewhite solid title compound salt was obtained.

Calculated for C₂₄ H₂₂ N₃ O₂ Cl+0.7 HCl+0.125 H₂ O (MW=447.69): C,64.39; H, 5.17; N, 9.39; Cl, 13.46. Found: C, 64.26; H, 5.15; N, 9.33;Cl, 13.22.

Example 44

1,1-dimethylethyl 4-(3-thienylmethyl)-1-piperazinecarboxylate ##STR52##

A sample of t-butyloxycarbonyl piperazine (1.0 g, 5.4 mmol) wasdissolved in 10 mL of MeOH. 3-thiophenylcarboxaldehyde (0.72 g, 6.4mmol) was added to the stirred homogeneous solution maintained under anargon atmosphere and at room temperature. After stirring for 10 minutes,sodium cyanoborohydride (0.68 g, 10.8 mmol) was added to the solution,and this mixture was allowed to stir for 48 hours. To this mixture wasadded 20 mL of 6N HCl. Following cessation of gas evolution (20 minutes)the reaction mixture was partitioned between water and Et₂ O. The Et₂ Owas separated and the aqueous was brought to pH 10.5 with NH₄ OH. Theaqueous layer was extracted with 3×100 mL of EtOAc. The crude titleproduct was isolated by drying the EtOAc solution over Na₂ SO₄ andremoving the solvent under reduced pressure. This material was used insubsequent reactions without further purification.

Example 45

1-(3-thienylmethyl)-1-piperazine, monohydrochloride ##STR53##

The title compound of Example 44 (0.58 g, 2.0 mmol) was converted to thetitle product by the method of Example 31. A 0.35 g sample of thismaterial was obtained.

Example 46

8-chloro-10,11-dihydro-10-[[4-(3-thienylmethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR54##

The title compound of Example 2 (0.57 g, 1.90 mmol) was combined withthe title product of Example 45 (0.35 g, 1.90 mmol) and the reaction wascarried out by the method of Example 4 with the modification of Example32. Following chromatographic separation, 1.7 g of the white solid titleproduct was obtained.

Calculated for C₂₃ H₂₂ N₃ O₂ SCl+0.05 CH₂ Cl₂ (MW=444.21): C, 62.32; H,5.01; N, 9.46; S, 7.22; Cl, 8.78. Found: C, 62.34; H, 5.13; N, 9.30; S,7.38; Cl, 8.70.

Example 47

8-chloro-10,11-dihydro-10-[[4-(3-thienylmethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR55##

The title material was synthesized from the title material of Example 46(0.24 g, 3.0 mmol) by the method of Example 5. A 0.21 g sample of thewhite solid title compound salt was obtained.

Calculated for C₂₃ H₂₂ N₃ O₂ SCl+HCl (MW=476.25): C, 57.98; H, 4.87; N,8.82; S, 6.73; Cl, 14.88. Found: C, 58.29; H, 4.92; N, 8.89; S, 6.46;Cl, 13.90.

Example 48

8-chloro-10,11-dihydro-10-[[2-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR56##

The title compound of Example 2 (1.25 g, 4.25 mmol) was combined with2-(2-pyrrolidinoethyl)piperadine (0.82 g, 4.50 mmol) and the reactionwas carried out by the method of Example 4. Following chromatographicseparation, 0.41 g of the white solid title product was obtained.

Calculated for C₂₅ H₃₀ N₃ O₂ Cl+0.1 CH₂ Cl₂ +0.5 H₂ O (MW=457.49): C,65.90; H, 6.87; N, 9.19; Cl, 9.30. Found: C, 66.19; H, 6.72; N, 9.14;Cl, 9.44.

Example 49

8-chloro-10,11-dihydro-10-[[2-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]carbonyl]dibenz[b,f][1,4]oxazepine,hydrochloride ##STR57##

The title material was synthesized from the title material of Example 48(0.24 g, 3.0 mmol) by the method of Example 5. A 0.21 g sample of thewhite solid title compound salt was obtained.

Calculated for C₂₅ H₃₀ N₃ O₂ Cl+1.1 HCl+1.5 H₂ O (MW=507.12): C, 59.21;H, 6.78; N, 8.29; Cl, 8.29. Found: C, 59.11; H, 6.44; N, 8.09; Cl,14.92.

Example 50

ethyl4-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-1-phenyl-2-piperazinecarboxylate##STR58##

N-phenylethylenediamine (24.4 g, 0.18 mole) and benzylaldehyde (19.1 g,0.18 mole) were mixed neat, let stand for 1 hour, diluted with Et₂ O,and dried over Na₂ SO₄. Removal of the solvent under reduced pressuregave 34.5 g of N-phenyl-N'-phenylmethylenyl-1,2-ethanediamine.

To a 5.0 g (22.3 mmol) sample of this material dissolved in 80 mL ofethanol was added 3.0 g of NaBH₄ (78.9 mmol) portionwise to the stirredreaction. After 3 hours at room temperature, all solvent was strippedunder reduced pressure and the residue was dissolved in dilute HCl. Thismixture was filtered and the filtrate was made basic with dilute NaOHbefore extracting with Et₂ O. This extract was dried over Na₂ SO₄ andstripped of all solvent to provide 3.9 g of the desiredN-phenyl-N'-(phenylmethyl)-1,2-ethanediamine.

A mixture of this ethylenediamine (31 g, 0.137 mole) and triethylamine(28 g, 0.277 mole) was added dropwise over 30 minutes to a stirredsolution of ethyl-2,3-dibromopropionate (35.0 g, 0.135 mole) dissolvedin 200 mL of toluene and heated to 40° C. After the addition wascomplete, the reaction was heated at 80°-85° C. for 7 hours, cooled toroom temperature, and partitioned between water and toluene. The organiclayer was separated, dried, and stripped of all solvent under reducedpressure to yield 38 g of the crude product. Chromatographicpurification gave 12.8 g of ethyl1-phenyl-4-(phenylmethyl)-2-piperazinecarboxylate.

An EtOH (75 mL) solution of ethyl1-phenyl-4-(phenylmethyl)-2-piperazinecarboxylate (2.20 g, 6.8 mmol) and500 mg of 4% Pd/C was subjected to hydrogenolysis in a standard Parrapparatus. The reaction was carried out for 10 hours at 55° C. and undera hydrogen pressure of 5 psi. After the catalyst was removed byfiltration and the solvent by stripping under reduced pressure, 1.5 g ofethyl 1-phenyl-2-piperazinecarboxylate was obtained as a clear oil.

The title compound of Example 2 (1.8 g, 6.30 mmol) was reacted withethyl 1-phenyl-2-piperazinecarboxylate (0.82 g, 4.50 mmol) by the methodof Example 4. Following chromatographic separation, 2.66 g of the whitesolid title product was obtained.

Calculated for C₂₇ H₂₆ N₃ O₄ Cl+0.5 CH₂ Cl₂ (MW=496.22): C, 65.47; H,5.30; N, 8.47; Cl, 7.86. Found: C, 65.27; H, 5.18; N, 8.48; Cl, 7.94.

Example 51

1,1-dimethylethyl 4-(2-thienylmethyl)-1-piperazinecarboxylate ##STR59##

The title material was synthesized from t-butyloxycarbonyl piperazine(1.0 g, 5.4 mmol) and 2-thiophenylcarboxaldehyde (0.72 g, 6.4 mmol) bythe method of Example 44. A 0.56 g sample of the crude title materialwas obtained and used without further purification.

Example 52

1-(2-thienylmethyl)piperazine, monohydrochloride ##STR60##

The title compound of Example 51 (0.56 g, 2.0 mmol) was converted to thetitle product by the method of Example 31. A 0.57 g sample of thismaterial was obtained.

Example 53

8-chloro-10,11-dihydro-10-[[4-(2-thienylmethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR61##

The title compound of Example 2 (0.93 g, 3.20 mmol) was reacted with theproduct of Example 52 (0.57 g, 3.20 mmol) by the method of Example 4with the modification described in Example 32. Following chromatographicseparation, 0.26 g of the white solid title product was obtained.

Calculated for C₂₃ H₂₂ N₃ O₂ SCl (MW=439.96): C, 62.79; H, 5.04; N,9.55; S, 7.29; Cl, 8.06. Found: C, 62.67; H, 5.22; N, 9.50; S, 6.75; Cl,8.06.

Example 54

8-chloro-10,11-dihydro-10-[[4-(2-thienylmethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR62##

The title material was synthesized from the title material of Example 53(0.24 g, 3.0 mmol) by the method of Example 5. A 0.21 g sample of thewhite solid title compound salt was obtained.

Calculated for C₂₃ H₂₂ N₃ O₂ SCl+HCl 3/8 H₂ O (MW=483.18): C, 57.17; H,4.95; N, 8.57; S, 6.64; Cl, 14.67. Found: C, 57.27; H, 4.90; N, 8.70; S,6.64; Cl, 13.97.

Example 55

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-(3-pyridinylacetyl)piperazine##STR63##

The title compound of Example 25 (1.5 g, 3.8 mmol) and1-(3-pyridinylacetyl)piperazine (0.67 g, 3.8 mmol) were dissolved in 20mL of DMF. To this magnetically stirred homogeneous solution cooled to-5° C. under an argon atmosphere were added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.73 g, 3.8mmol), 1-hydroxy benzotriazole hydrate (0.51 g, 3.8 mmol) and triethylamine (1.15 g, 11.4 mmol). The reaction mixture was allowed to slowlywarm to room temperature and stirred an additional 16 hours before allsolvent was removed under reduced pressure. The residue was dissolved inEtOAc (300 mL) and this solution was washed with 2×75 mL of 0.5M K₂ CO₃and 2×75 mL of brine, dried (Na₂ SO₄), and stripped of all solvent invacuo. Following chromatography, 1.56 g of the title product as a whitesolid was obtained.

Calculated for C₂₅ H₂₃ N₄ O₃ Cl (MW=474.49): C, 63.36; H, 5.11; N,11.81; Cl, 7.92. Found: C, 63.49; H, 5.00; N, 11.70; Cl, 8.23.

Example 56

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-(3-pyridinylacetyl)piperazine,monohydrochloride ##STR64##

The title material was synthesized from the title material of Example 55(1.26 g, 2.65 mmol) by the method of Example 5. A 1.32 g sample of thewhite solid title compound salt was obtained.

Calculated for C₂₅ H₂₃ N₄ O₃ Cl+HCl+0.75 H₂ O (MW=512.91): C, 58.54; H,5.01; N, 10.92; Cl, 13.82. Found: C, 58.56; H, 4.98; N, 10.65; Cl,14.32.

Example 57

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-(3-pyridinylcarbonyl)piperazine##STR65##

The title compound of Example 25 (0.5 g, 1.32 mmol) was coupled to3-pyridine carboxylic acid (0.16 g, 1.32 mmol) by the procedure ofExample 55. Following chromatographic separation of the crude product,0.52 g of the title compound was obtained.

Example 58

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-(3-pyridinylcarbonyl)piperazine,hydrochloride ##STR66##

The title compound of Example 57 (0.45 g, 0.95 mmol) was converted tothe title product by the method of Example 17. A 0.37 g sample of thismaterial was obtained.

Calculated for C₂₄ H₂₁ N₄ O₃ Cl+0.3 HCl+0.3 H₂ O (MW=465.25): C, 61.96;H, 4.74; N, 12.04; Cl, 9.91. Found: C, 61.66; H, 4.73; N, 11.87; Cl,10.19.

Example 59

ethyl4-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]hexahydro-1H-1,4-diazepine-1-carboxylate##STR67##

The title compound of Example 2 (2.0 g, 6.80 mmol) was reacted with theproduct of Example 96 (ethylhexahydro-1H-1,4-diazacycloheptane-1-carboxylate) (1.29 g, 7.48 mmol) bythe method of Example 4. Following chromatographic separation, 3.0 g ofthe yellow oil crude title product was obtained.

Calculated for C₂₂ H₂₄ N₃ O₄ Cl (MW=429.91): C, 61.47; H, 5.63; N, 9.77;Cl, 8.25. Found: C, 61.28; H, 5.82; N, 9.55; Cl, 8.01.

Example 60

8-chloro-10-[(hexahydro-1H-1,4-diazepin-1-yl)carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine##STR68##

The title product of Example 59 (2.5 g, 5.8 mmol) was combined with 25mL of concentrated HCl and 25 mL of dioxane. The solution was brought toreflux and maintained at reflux and under N₂ for 6 days. After coolingthe reaction to room temperature, all solvent was removed in vacuo andthe residue was dissolved in EtOAc. This solution was brought to pH 8with 2N NaOH and the organic solution was dried, filtered, and strippedof all solvent under reduced pressure. The residue was purified bychromatography to give 1.0 g of the title compound.

Example 61

8-chloro-10-[(hexahydro-1H-1,4-diazepin-1-yl)carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine,hydrochloride ##STR69##

The title compound of Example 60 (0.20 g, 0.56 mmol) was converted tothe title product by the method of Example 17. A 0.14 g sample of thismaterial was obtained.

Calculated for C₁₉ H₂₀ N₃ O₂ Cl+1.1 HCl+0.2 H₂ O (MW=401.55): C, 54.65;H, 5.19; N, 10.06; Cl, 17.83. Found: C, 54.41; H, 5.21; N, 9.85; Cl,18.03.

Example 62

1,1-dimethylethyl 4-(2-furanylmethyl)-1-piperazinecarboxylate ##STR70##

The title material was synthesized from t-butyloxycarbonyl piperazine(1.0 g, 5.4 mmol) and 2-furancarboxaldehyde (0.62 g, 6.5 mmol) by themethod of Example 44. A 0.34 g sample of the crude title material wasobtained and used without further purification.

Example 63

1-(2-furanylmethyl)piperazine hydrachloride ##STR71##

The title compound of Example 62 (0.34 g, 1.7 mmol) was converted to thetitle product by the method of Example 31. A 0.50 g sample of thismaterial was obtained.

Example 64

8-chloro-10-[[4-(2-furanylmethyl)-1-piperazinyl]carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine##STR72##

The title compound of Example 2 (0.91 g, 3.10 mmol) was reacted with theproduct of Example 63 (0.50 g, 3.10 mmol) by the method of Example 4with the modification described in Example 32. Following chromatographicseparation, 0.09 g of the solid title product was obtained.

Calculated for C₂₃ H₂₂ N₃ O₃ Cl+0.5 H₂ O+0.3 CH₂ Cl₂ (MW=458.34): C,61.05; H, 5.19; N, 9.17; Cl, 12.37. Found: C, 60.71; H, 5.10; N, 9.16;Cl, 12.75.

Example 65

8-chloro-10-[[4-(2-furanylmethyl)-1-piperazinyl]carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine,monohydrochloride ##STR73##

The title material was synthesized from the title material of Example 64(0.09 g, 0.020 mmol) by the method of Example 5. A 0.056 g sample of thecream colored solid title compound salt was obtained.

Calculated for C₂₃ H₂₂ N₃ O₃ Cl+HCl 0.5 H₂ O (MW=469.37): C, 58.86; H,5.15; N, 8.95. Found: C, 58.53; H, 5.06; N, 8.86.

Example 66 COMPOUND A

8-chloro-10-[[4-[2-(diethylamino)ethyl]-3,6-dihydro-1(2H)-pyridinyl]carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine##STR74##

COMPOUND B

8-chloro-10-[[4-[2-(diethylamino)ethyl]-1-piperidinyl]carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine##STR75##

The title compound of Example 2 (1.5 g, 5.10 mmol) was reacted with amixture of N,N-diethyl-1,2,3,6-tetrahydro-4-pyridinethanamine andN,N-diethyl-4-piperidineethanamine (0.95 g, 5.10 mmol) by the method ofExample 4. Following chromatographic separation, 0.88 g of the solidCOMPOUND A title product and 1.29 g of a mixture of title COMPOUNDS Aand B were obtained.

COMPOUND A

Calculated for C₂₄ H₃₀ N₃ O₂ Cl+0.03 CH₂ Cl₂ (MW=430.52): C, 67.04; H,7.04 N, 9.76 Cl, 8.73. Found: C, 67.10; H, 6.90; N, 9.31; Cl, 8.80.

Example 67

8-chloro-10-[[4-[2-(diethylamino)ethyl]-3,6-dihydro-1(2H)-pyridinyl]carbonyl]-10,11-dihydeodibenz[b,f][1,4]oxazepine,hydrochloride ##STR76##

The title material was synthesized from of the title material of Example66 (COMPOUND A) (0.09 g, 0.020 mmol) by the method of Example 5. A 0.056g sample of the cream colored solid title compound salt was obtained.

Calculated for C₂₄ H₃₀ N₃ O₂ Cl+0.125 H₂ O+0.02 CH₂ Cl₂ (MW=430.92): C,66,95; H, 6.85; N, 9.75 Cl, 8.58. Found: C, 67.10; H, 6.90; N, 9.31; Cl,8.80.

Example 68

1-[[4-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-1-piperazinyl]acetyl]pyrrolidine##STR77##

The title compound of Example 2 (0.75 g, 2.55 mmol) was reacted with1-(1-piperazinylacetyl)pyrrolidine (0.50 g, 2.55 mmol) by the method ofExample 4. Following chromatographic separation, 1.08 g of clear oiltitle product was obtained.

Example 69

1-[[4-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-1-piperazinyl]acetyl]pyrrolidine,hydrochloride ##STR78##

The title material was synthesized from the title material of Example 68(0.95 g, 2.10 mmol) by the method of Example 5. A 0.84 g sample of thesolid title compound salt was obtained.

Calculated for C₂₄ H₂₇ N₄ O₃ Cl+1.4 HCl+1.5 H₂ O (MW=430.52): C, 54.08;H, 5.94; N, 10.51; Cl, 15.96. Found: C, 53.79; H, 5.64; N, 10.37; Cl,15.99.

Example 70

8-chloro-10-[[4-(dimethylamino)-1-piperidinyl]carbonyl]-10,11-dihydrodibenz[b,f][1,4oxazepine##STR79##

The title compound of Example 2 (1.0 g, 3.40 mmol) was reacted withN,N-dimethyl-4-piperidinamine (0.48 g, 3.74 mmol) by the method ofExample 4. Following chromatographic separation, 0.32 g of the titleproduct was obtained.

Example 71

8-chloro-10-[[4-(dimethylamino)-1-piperidinyl]carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine,monohydrochloride ##STR80##

The title material was synthesized from the title product of Example 70(0.30 g, 0.78 mmol) by the method of Example 5. A 0.84 g sample of thesolid title compound salt was obtained.

Calculated for C₂₁ H₂₄ N₃ O₂ Cl+1.1 HCl+0.5 H₂ O (MW=435.01): C, 58.12;H, 5.83; N, 9.68; Cl, 17.15. Found: C, 58.17; H, 5.65; N, 9.56; Cl,17.03.

Example 72

1,1-dimethylethyl 4-(3-furanylmethyl)-1-piperazinecarboxylate ##STR81##

The title material was synthesized from t-butyloxycarbonyl piperazine(1.0 g, 5.4 mmol) and 3-furancarboxaldehyde (0.62 g, 6.4 mmol) by themethod of Example 44. A 0.69 g sample of the crude title material wasobtained and used without further purification.

Example 73

1-(3-furanylmethyl)piperazine hydrachloride ##STR82##

The title compound of Example 72 (0.69 g, 2.6 mmol) was converted to thetitle product by the method of Example 31. A 0.16 g sample of thismaterial was obtained.

Example 74

8-chloro-10-[[4-(3-furanylmethyl)-1-piperazinyl]carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine##STR83##

The title compound of Example 2 (0.29 g, 0.98 mmol) was reacted with theproduct of Example 73 (0.16 g, 0.98 mmol) by the method of Example 4with the modification described in Example 32. Following chromatographicseparation, 0.08 g of the solid title product was obtained.

Calculated for C₂₃ H₂₂ N₃ O₃ Cl+0.25 H₂ O+0.45 CH₂ Cl₂ (MW=466.62): C,60.36; H, 5.05; N, 9.01; Cl, 14.44. Found: C, 60.05; H, 5.05; N, 8.93;Cl, 14.77.

Example 75

8-chloro-10-[[4-(3-furanylmethyl)-1-piperazinyl]carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine,monohydrochloride ##STR84##

The title material was synthesized from the title material of Example 74(0.06 g, 0.013 mmol) by the method of Example 5. A 0.023 g sample of thewhite solid title compound salt was obtained.

Calculated for C₂₃ H₂₂ N₃ O₃ Cl+HCl 1.5 H₂ O (MW=487.38): C, 56.68; H,5.38; N, 8.62; Cl, 14.55. Found: C, 56.55; H, 4.96; N, 8.51; Cl, 14.40.

Example 76

8-chloro-10,11-dihydro-10-[[4-(4-pyridinylmethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR85##

The title compound of Example 25 (1.5 g, 3.6 mmol) and 4-pyridinecarboxaldehyde (excess) were reacted by the method of Example 39 togenerate, after chromatographic purification, 87 mg of the titlecompound.

Calculated for C₂₄ H₂₃ N₄ O₂ Cl+0.01 CH₂ Cl₂ +1.0 H₂ O (MW=453.79): C,63.55; H, 5.56; N, 12.35; Cl, 7.97. Found: C, 63.41; H, 5.54; N, 12.99;Cl, 7.99.

Example 77

8-chloro-10,11-dihydro-10-[[4-(4-pyridinylmethyl)-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR86##

The title material was synthesized from the title product of Example 76(0.05 g, 0.11 mmol) by the method of Example 5. A 0.025 g sample of thesolid title compound salt was obtained.

Calculated for C₂₄ H₂₃ N₄ O₂ Cl+1.0 HCl+0.5 H₂ O (MW=480.40): C, 60.01;H, 5.25; N, 11.66; Cl, 14.76. Found: C, 59.77; H, 5.33; N, 11.63; Cl,14.77.

Example 78

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-(4-pyridinylacetyl)piperazine##STR87##

The title compound of Example 25 (1.38 g, 3.64 mmol) was coupled to4-pyridyl acetic acid (0.63 g, 3.64 mmol) by the procedure of Example55. Following chromatographic separation of the crude product, 0.91 g ofthe title compound was obtained as a white solid.

Example 79

1-[(8-Chlorodibenz[b,f][1,4]oxozepin-10(11H)-yl)carbonyl]-4-[1-oxo-2(4-pyridinyl)ethyl]piperazine,monohydrochloride, monohydrate ##STR88##

The title compound was synthesized from the title product of Example 78(0.50 g, 1.08 mmol) by the method of Example 17. A 0.50 g sample of thewhite fluffy solid title product was obtained.

Calculated for C₂₅ H₂₃ N₄ O₃ Cl+1.0 HCl+1.0 H₂ O (MW=517.42): C, 58.03;H, 5.07; N, 10.83; Cl, 13.70. Found: C, 58.28; H, 4.93; N, 10.80; Cl,13.44.

Example 80

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]hexahydro-4-(4-pyridinylacetyl)-1H-1,4-diazepine##STR89##

The title compound of Example 61 (1.43 g, 3.64 mmol) was coupled to4-pyridyl acetic acid (0.63 g, 3.64 mmol) by the procedure of Example55. Following chromatographic separation of the crude product, 0.56 g ofthe title compound was obtained as a white solid.

Example 81

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]hexahydro-4-(4-pyridinylacetyl)-1H-1,4-diazepine,monohydrochloride ##STR90##

The title compound was synthesized from the title product of Example 80(0.50 g, 1.08 mmol) by the method of Example 17. A 0.50 g sample of thewhite fluffy solid title product was obtained.

Calculated for C₂₆ H₂₅ N₄ O₃ Cl+1.0 HCl+0.25 H₂ O (MW=517.93): C, 60.30;H, 5.16; N, 10.82; Cl, 13.69. Found: C, 60.32; H, 5.45; N, 10.90; Cl,13.20.

Example 82

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-[[5-(2-pyridinyl)-2-thienyl]carbonyl]piperazine##STR91##

The title compound of Example 25 (1.5 g, 3.85 mmol) was coupled to5-(pyrid-2-yl)thiophene-2-carboxylic acid (1.5 g, 3.85 mmol) by theprocedure of Example 55. Following chromatographic separation of thecrude product, 0.84 g of the title compound was obtained as a whitesolid.

Calculated for C₂₈ H₂₃ N₄ O₃ SCl+0.75 H₂ O (MW=544.55): C, 61.76; H,4.54; N, 10.29; S; 5.89; Cl, 6.51. Found: C, 61.89; H, 4.22; N, 10.12;S, 5.91; Cl, 5.91.

Example 83

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-[[5-(2-pyridinyl)-2-thienyl]carbonyl]piperazinehydrochloride ##STR92##

The title material was synthesized from the title material of Example 82(0.74 g, 1.36 mmol) by the method of Example 5. A 0.50 g sample of thewhite solid title compound salt was obtained.

Calculated for C₂₈ H₂₃ N₄ O₃ SCl+HCl+H₂ O (MW=585.51): C, 57.44; H,4.63; N, 9.57; S; 5.48; Cl, 12.11. Found: C, 57.71; H, 4.36; N, 9.69; S,5.64; Cl, 12.52.

Example 84

Ethyl 2-thiophenepropionate ##STR93##

Ethylacrylate (10.0 g, 100 mmol), 2-bromothiophene (16.3 g, 100 mmol),palladium(II) acetate (0.5 g, 2.22 mmol), and tri-o-tolylphosphine (1.62g, 5.4 mmol) were dissolved in a mixture of triethylamine (40 mL) andacetonitrile (140 mL). This solution was refluxed under nitrogen (N₂)for 17 hours before it was diluted with EtOAc (250 mL) and H₂ O (115mL). This mixture was filtered through celite and the aqueous layerdiscarded. The organic layer was washed with 1×75 mL of H₂ O and 2×75 mLof brine, dried over Na₂ SO₄ and stripped of all solvent under reducedpressure to provide 22.3 g of crude product, The unsaturated2-thiophenyl ethyl ester material, 13.9 g as a pale yellow liquid, wasobtained after chromatographic purification.

A 7.0 g sample of this material was reduced to the title product in aStandard Parr hydrgenation apparatus using 10% Pd on carbon as catalystand ethanol as solvent. The reaction was run at room temperature for 23hours under a hydrogen pressure of 5 psi. The reaction mixture was thenfiltered and all solvent was removed under reduced pressure to yield 2.9g of the crude title product. This material was used in Example 85without further purification.

Example 85

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-[1-oxo-3-(2-thienyl)propyl]piperazine##STR94##

The title product of Example 25 (1.0 g, 2.57 mmol) and triethyl amine(0.26 g, 2.57 mmol) were dissolved in 30 mL of methylene chloride. Tothis solution was added trimethyl aluminum (2.0M in hexane, 1.6 mL, 3.08mmol) and the product of Example 84 (0.57 g, 2.72 mmol). This mixturewas refluxed under N₂ for 3 days before it was cooled to roomtemperature and partitioned between EtOAc (300 mL) and 0.5N KHSO₄ (75mL). The aqueous layer was discarded and the organic layer was washedwith 100 mL of brine, dried over Na₂ SO₄ and stripped of all solventunder reduced pressure to provide the crude product. The title product(0.45 g) was obtained as a white solid following chromatographicpurification.

Calculated for C₂₅ H₂₄ N₃ O₃ SCl+0.125 H₂ O+0.01 CH₂ Cl₂ (MW=485.10): C,61.92; H, 5.04; N, 8.66; S; 6.61; Cl, 7.45. Found: C, 61.91; H, 5.15; N,8.60; S, 6.64; Cl, 7.73.

Example 86

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]hexahydro-4-[1-oxo-3-(3-pyridinyl)propyl]-1H-1,4-diazepine##STR95##

The title compound of Example 60 (0.73 g, 2.0 mmol) was coupled to3-(3-pyridyl)propanoic acid (0.31 g, 2.0 mmol) by the procedure ofExample 55. Following chromatographic separation of the crude product,0.60 g of the title compound was obtained as a white solid and used inExample 87 without further purification.

Example 87

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]hexahydro-4-[1-oxo-3-(3-pyridinyl)propyl]-1H-1,4-diazepine,monohydrochloride ##STR96##

The title compound was synthesized from the title product of Example 86(0.25 g, 0.51 mmol) by the method of Example 17. A 0.25 g sample of theslightly off white fluffy solid title product was obtained.

Calculated for C₂₇ H₂₇ N₄ O₃ Cl+1.0 HCl+0.40 H₂ O (MW=534.66): C, 60.66;H, 5.43; N, 10.48; Cl, 13.26. Found: C, 60.69; H, 5.53; N, 10.47; Cl,12.88.

Example 88

1-[2-(4-pyridinyl)ethyl]piperazine ##STR97##

To a melt of piperazine (15 g, 0.17 mol) heated to 105° C. was addeddropwise 4-vinylpyridine (1.25 mL, 0.012 mol). After refluxing thereaction for 5.5 hours, it was cooled to room temperature andchromatographed to provide 0.92 g of the title compound.

Example 89

8-chloro-10,11-dihydro-10-[[4-[2-(4-pyridinyl)ethyl]-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR98##

The title compound of Example 2 (0.38 g, 1.3 mmol) was combined with theproduct of Example 88 (0.25 g, 1.3 mmol) and the reaction was carriedout by the method of Example 4. Following chromatographic separation,1.7 g of the white solid title product was obtained.

Example 90

8-chloro-10,11-dihydro-10-[[4-[2-(4-pyridinyl)ethyl]-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR99##

The title compound was synthesized from the title product of Example 89(0.36 g, 0.80 mmol) by the method of Example 17. A 0.38 g sample of thewhite fluffy solid title product was obtained.

Calculated for C₂₅ H₂₅ N₄ O₂ Cl+1.7 HCl+0.7 H₂ O (MW=523.55): C, 57.35;H, 5.41; N, 10.70; Cl, 18.28. Found: C, 57.49; H, 5.43; N, 10.39; Cl,18.01.

Example 91

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-[(6-quinolinyl)carbonyl]piperazine##STR100##

The title compound of Example 25 (1.5 g, 3.85 mmol) was coupled to6-quinolinecarboxylic acid (0.67 g, 3.85 mmol) by the procedure ofExample 55. Following chromatographic separation of the crude product,1.23 g of the title compound was obtained as a white solid.

Calculated for C₂₈ H₂₃ N₄ O₃ Cl+0.1 CH₂ Cl₂ +0.15 EtOAc (MW=520.52): C,65.88; H, 4.67; N, 10.76; Cl, 8.85. Found: C, 65.64; H, 4.65; N, 10.86;Cl, 8.81.

Example 92

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]hexahydro-4-[(6-quinolinyl)carbonyl]-1H-1,4-diazepine##STR101##

The title compound of Example 61 (1.58 g, 4.0 mmol) was coupled to6-quinolinecarboxylic acid (0.69 g, 4.0 mmol) by the procedure ofExample 55. Following chromatographic separation of the crude product,1.35 g of the title compound was obtained as a white solid.

Calculated for C₂₉ H₂₅ N₄ O₃ Cl+0.2 H₂ O (MW=516.60): C, 67.43; H, 4.96;N, 10.85; Cl, 6.86. Found: C, 67.31; H, 4.90; N, 10.73; Cl, 6.97.

Example 93

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]hexahydro-4-[(6-quinolinyl)carbonyl]-1H-1,4-diazepine,monohydrochloride ##STR102##

The title compound was synthesized from the title material of Example 92(0.50 g, 0.97 mmol) by the method of Example 17. A 0.42 g sample of thewhite fluffy solid title product was obtained.

Calculated for C₂₅ H₂₅ N₄ O₂ Cl+1.7 HCl+0.7 H₂ O (MW=523.55): C, 57.35;H, 5.41; N, 10.70; Cl, 18.28. Found: C, 57.49; H, 5.43; N, 10.39; Cl,18.01.

Example 94

Ethyl 4-pyridinepropanoate ##STR103##

Ethylacrylate (10.0 g, 100 mmol), 4-bromopyridine (19.4 g, 100 mmol),palladium(II) acetate (0.5 g, 2.22 mmol), and tri-o-tolylphosphine (1.62g, 5.4 mmol) in a mixture of triethylamine (40 mL) and acetonitrile (140mL) were reacted as described in Example 84. The unsaturated 4-pyridylethyl ester product, 15.0 g as a clear liquid, was obtained afterchromatographic purification.

A 7.5 g (42.3 mmol) sample of this material was reduced to the titleproduct in a Standard Parr hydrgenation apparatus using raney nickel ascatalyst and ethanol as solvent. The reaction was run at roomtemperature for 23 hours under a hydrogen pressure of 5 psi. Thereaction mixture was then filtered and all solvent was removed underreduced pressure to yield 7.02 g of the crude title product. Thismaterial was used in the following reaction without furtherpurification.

Example 95

1-[(8-chlorodibenz[b,f][1,4]oxazepin-10(11H)-yl)carbonyl]-4-[1-oxo-3-(4-pyridinyl)-propyl]piperazine##STR104##

The product of Example 94 (0.46 g, 2.57 mmol) and the product of Example25 (1.0 g, 2.57 mmol) were reacted as described in Example 85. Followingsilica gel chromatropraphy, 0.39 g of the title compound was isolated asa white powder.

Calculated for C₂₆ H₂₅ N₄ O₃ Cl+0.05 CH₂ Cl₂ +0.125 H₂ O (MW=483.46): C,64.72; H, 5.29; N, 11.59 Cl, 8.07. Found: C, 64.83; H, 5.30; N, 11.60;Cl, 8.11.

Example 96

Ethyl hexahydro-1H-1,4-diazepine-1-carboxylate ##STR105##

To a solution of homopiperazine (50.0 g, 0.5 mol) in aqueous HCladjusted to pH 4 using approximately 400 mL of 2N HCl was added ethylchloroformate (50 mL, 0.53 mol) dropwise maintaining the pH at 4 by theaddition of 25% aqueous NaOH. The reaction mixture was brought to pH 14with 25% aqueous NaOH and extracted with 3×250 mL of Et₂ O. Theseextracts were discarded and the aqueous was brought to pH 10 with 2N HCland Na₂ CO₃. After extracting the aqueous with 3×150 mL of Et₂ O, thesecombined extracts were dried over Na₂ SO₄, and stripped of all solventunder reduced pressure. The residue was vacuum distilled at 0.1 mm of Hgand the title compound was obtained as the fraction (25.0 g) distillingat 103° C.

Example 97

Ethyl hexahydro-4-(2-phenylethyl)-1H-1,4-diazepine-1-carboxylate##STR106##

The product of Example 96 (0.75 g, 4.35 mmol) and phenylacetaldehyde(0.59 g, 4.91 mmol) were reacted as described in Example 39. The titleproduct (1.07 g) was obtain as a light yellow liquid after work up andwas used in Example 98 without further purification.

Example 98

Hexahydro-1-(2-phenylethyl)-1H-1,4-diazepine ##STR107##

The title material of Example 97 (0.80 g, 2.90 mmol) was dissolved in 20mL of concentrated HCl and heated to reflux for 18 hours. After coolingthe reaction to room temperature, it was diluted with 15 mL of water andmade basic with 2N NaOH. This mixture was extracted with EtOAc and thisEtOAc solution was dried over Na₂ SO₄ and stripped of all solvent underreduced pressure to provide 0.53 g of the title material as a yellowoil. This product was used in subsequent reactions without furtherpurification.

Example 99

8-chloro-10,11-dihydro-10-[[hexahydro-4-(2-phenylethyl)-1H-1,4-diazepin-1-yl]carbonyl]dibenz[b,f][1,4]oxazepine##STR108##

The title compound of Example 2 (0.72 g, 2.45 mmol) was combined withthe title material of Example 98 (0.50 g, 2.45 mmol) and the reactionwas carried out by the method of Example 4. Following chromatographicseparation, 0.63 g of the white solid title product was obtained.

Example 100

8-chloro-10,11-dihydro-10-[[hexahydro-4-(2-phenylethyl)-1H-1,4-diazepin-1-yl]carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR109##

The title compound was synthesized from the title material of Example 99(0.62 g, 1.35 mmol) by the method of Example 17. A 0.05 g sample of thewhite fluffy solid title product was obtained.

Calculated for C₂₇ H₂₈ N₃ O₂ Cl+1.5 HCl+2.0 H₂ O (MW=552.72): C, 58.67;H, 6.11; N, 7.60; Cl, 16.04. Found: C, 58.79; H, 5.68; N, 7.56; Cl,15.90.

Example 101

8-chloro-10,11-dihydro-10-[[4-[2-[(phenylmethyl)amino]ethyl]-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR110##

The title compound of Example 2 (0.72 g, 2.45 mmol) was combined withN-(phenylmethyl)-1-piperazineethanamine (0.75 g, 3.40 mmol) and thereaction was carried out by the method of Example 4. Followingchromatographic separation, 0.52 g of the white solid title product wasobtained.

Example 102

8-chloro-10,11-dihydro-10-[[4-[2-[(phenylmethyl)amino]ethyl]-1-piperazinyl]carbonyl]dibenz[b,f][1,4]oxazepine,monohydrochloride ##STR111##

The title compound was synthesized from the title material of Example101 (0.37 g, 0.81 mmol) by the method of Example 17. A 0.05 g sample ofthe white fluffy solid title product was obtained.

Calculated for C₂₆ H₂₈ N₅ O₂ Cl+2.9 HCl+1.5 H₂ O (MW=610.76): C, 51.13;H, 5.59; N, 11.47; Cl, 22.64. Found: C, 51.23; H, 5.54; N, 11.29; Cl,22.61.

Example 103

8-chloro-10-[[4-[2-(diethylamino)ethyl]piperidinyl]carbonyl]-10,11-dihydrodibenz[b,f][1,4]oxazepine##STR112##

The title material is synthesized from COMPOUND B of the title materialof Example 66 by the method of Example 5.

Example 104

8-chloro-10,11-dihydrodibenz[b,f][1,4]thiazepine ##STR113## (a)4-chloro-2-nitro-1-(phenylthio)benzene

Potassium hydroxide (6.15 g; 87%) was added to a stirred solution ofthiophenol (10.0 g) in N,N-dimethylformamide (170 mL) at roomtemperature. When most of the potassium hydroxide appeared to havedissolved, 2,5-dichloronitrobenzene (17.4 g) was added, and theinitially dark solution turned bright yellow with some precipitate. Thereaction was placed in an oil bath at 70° C. for three hours, and thenevaporated in vacuo. The residue was partitioned between chloroform and1N NaOH and the layers were separated. The aqueous layer was extractedonce more with chloroform. The chloroform solutions were combined,washed with 1N NaOH, H₂ O, 1N HCl, H₂ O and brine, dried over MgS₄, andevaporated in vacuo. The resulting oil was treated with cyclohexane, andthe product crystallized. The crystalline product was collected byfiltration, washed with hexane, and dried in vacuo at 56° C. to yield13.73 g (57%) of yellow crystals. mp: 84°-86° C.

(b) 5-chloro-2(phenylthio)benzenamine

A solution of 4-chloro-2-nitro-1-(phenylthio)benzene (11.0 g) and Raneynickel in ethanol (3A; 9.3 mL) was reacted in a Parr Hydrogenator underhydrogen atmosphere at 5 psi and room temperature. When the theoreticalamount of hydrogen uptake was reached, the reaction was filtered toremove the catalyst and evaporated in vacuo to yield 8.61 g (88%) of alight orange solid. mp: 59°-61° C.

(c) 8-chloro-10,11-dihydrodibenzo[b,f][1,4]thiazepine

To a cold (ice water bath), stirred solution of phosgene (1.93M intoluene; 55 mL) under a nitrogen atmosphere was added, dropwise, asolution of 5-chloro-2-(phenylthio)benzenamine (5.00 g) in toluene (20mL). The reaction mixture was stirred for 30 minutes in the ice bath,and was then heated on a steam bath for 30 minutes. The resulting orangesolution was evaporated in vacuo to an oil (IR: weak band atapproximately 2250 cm⁻¹).

The oil was taken up in bromobenzene (25 mL) and added dropwise to astirred mixture of aluminum chloride (2.90 g) in bromobenzene (25 mL) inan oil bath at 100° C. When the addition was complete, the oil bathtemperature was increased to 150° C., and the reaction was stirred for1.5 hours. A small amount of water was then added to quench thereaction, and the mixture was evaporated in vacuo. The residue wastriturated with acetone, and the solid was collected by filtration,washed with acetone followed by ether, and dried in vacuo at 110° C. for16 hours to yield 6.99 g of white solid.

The white solid (6.64 g) was suspended with stirring in anhydroustetrahydrofuran (175 mL) under a nitrogen atmosphere in an ice-H₂ Obath, and lithium aluminum hydride (1.0M in THF; 100 mL) was addeddropwise, keeping the temperature below 10° C. When the addition wascomplete, the ice bath was removed and the reaction was stirred to roomtemperature (approximately 20 minutes), and then at reflux for fourhours under a nitrogen atmosphere. The reaction was then cooled in anice-H₂ O bath and quenched by the successive addition of H₂ O (3.8 mL),15% NaOH (3.8 mL), and H₂ O (11.4 mL) while keeping the temperaturebelow 15° C. The resulting mixture was filtered through filter aide andthe filter cake was washed with THF. The filtrate and washes werecombined and evaporated in vacuo to a yellow oil. The oil was flashchromatographed through silica gel 60 (approximately 300 mL) usingchloroform. The collected product was recrystallized from cyclohexane toyield 2.37 g (42.7%) of product as white plates. mp: 125°-127° C.

Example 105

8-chlorodibenz[b,f][1,4]thiazepine-10(11H)-carbonyl chloride ##STR114##

To a cold (ice-H₂ O bath), stirred solution of phosgene (1.93M intoluene; 8.6 mL) in anhydrous tetrahydrofuran (40 mL) under a nitrogenatmosphere is added, dropwise, a solution of the product of Example 104(8-chloro-10,11-dihydrodibenzo[b,f][1,4]thiazepine) (2.00 g) andtriethylamine (1.3 mL) in anhydrous tetrahydrofuran (30 mL). Theresulting mixture is stirred at room temperature for 90 minutes, and thesolvent is then evaporated in vacuo to provide the title product.

Example 106

1-[(8-chlorodibenz[b,f][1,4]thiazepin-10(11H)-yl)carbonyl]-4-(2-furanylmethyl)piperazine##STR115##

The title compound of Example 105 is reacted with the product of Example63 by the method of Example 4. Following chromatographic separation, thetitle product is obtained.

Example 107

1-[(8-chlorodibenz[b,f][1,4]thiazepin-10(11H)-yl)carbonyl]-4-(2-furanylmethyl)piperazinemonohydrochloride ##STR116##

The title material is synthesized from the title material of Example 106by the method of Example 5.

Example 108

1-[(8-chlorodibenz[b,f][1,4]thiazepin-10(11H)-yl)carbonyl]-4-(2-furanylmethyl)piperazineS-oxide monohydrochloride ##STR117##

The title material is synthesized from the title material of Example 107by treatment of this compound with 30% H₂ O₂ in acetic acid at roomtemperature.

Example 109

1-[(8-chlorodibenz[b,f][1,4]thiazepin-10(11H)-yl-carbonyl]-4-(2-furanylmethyl)piperazineS,S-dioxide monohydrochloride ##STR118##

The title material is synthesized from the title material of Example 107by treatment of this compound with 30% H₂ O₂ in acetic acid at 50° C.

Example 110

8-chloro-10(11H)-[1-(phenylmethyl)-4-piperidinylmethyl]dibenz[b,f][1,4]thiazepine##STR119##

A sample of 1-benzylpiperidine-4-carboxylic acid ethyl ester is reducedto 1-benzylpiperidine-4-hydroxymethyl by treatment with lithium aluminumhydride (LiAlH₄) in THF. This material is converted to its methanesulfonate by reaction with methanesulfonyl chloride. This material,1-benzylpiperidine-4-methyl-methane sulfonate, the product of Example104, and diisopropylethyl amine are refluxed in toluene the provide thetitle compound.

Example 111

8-chloro-10(11H)-[1-(phenylmethyl)-4-piperidinylmethyl]dibenz[b,f][1,4]-thiazepinemonohydrochloride ##STR120##

The title material is synthesized from the title material of Example 110by the method of Example 5.

Example 112

8-chloro-10(11H)-[[1-(phenylmethyl)-4-piperidinyl]carbonyl]dibenz[b,f][1,4]oxazepine##STR121##

A sample of 1-benzylpiperidine-4-carboxylic acid ethyl ester is reactedin refluxing methylene chloride with the product of Example 104 andtrimethyl aluminum to yield the title product.

Example 113

8-chloro-10(11H)-[[1-(phenylmethyl)-4-piperidinyl]carbonyl]dibenz[b,f][1,4]oxazepinehydrochloride ##STR122##

The title material is synthesized from the title material of Example 112by the method of Example 5.

The foregoing examples are provided to enable one of ordinary skill inthe art to practice the present invention. These examples are merelyillustrative, however, and should not be read as limiting the scope ofthe invention as it is claimed in the appended claims.

Biological Assays

(a) The Writhing Assay

The Writhing Assay is one of the most widely-used experimentalprocedures for measuring the analgesic activity of different narcoticand nonnarcotic analgesic agents, and involves the continuous,chemically-induced pain of visceral origin to an animal, such as a mouseor rat. [Gyires et al., Arch. int. Pharmacodyn, 267, 131-140 (1984); C.Vander Wende et al., Fed. Proc., 15, 494 (1956); Koster et al., Fed.Proc., 18, 412 (1959); and Witken et al., J. Pharmacol. exp. Ther., 133,400-408 (1961).] Chemicals which may be used to induce this pain includephenylbenzoquinone (PBQ) and acetic acid. As a result of the chemicalirritation to the animal, a characteristic stretching and writhing ofthe animal (dorsiflexion of the animal's back, extension of itshindlimbs and the strong contraction of its abdominal musculature) willgenerally occur. The intensity of this pain reaction is determined bythe number of writhes exhibited by the animal during a given period oftime. Drugs which reduce the number of writhes of the animal appear torestore the normal nociceptive threshold of the animal.

Compounds of the present invention exhibit analgesic activity in mice,as shown by the results of the Writhing Assay presented in Table 1below.

Charles River male albino mice, weighing 20 to 30 grams were used inthis assay.

Twenty-five minutes after intragastric administration to nine or tenmice of 30 mg per kilogram of body weight of a compound of the presentinvention ("test compound"), 0.1 mg per 10 g of body weight of a 0.025%w/v solution of PBQ was injected intraperitoneally into each mouse. Tenmice which were given saline in place of a test compound of theinvention were used as a control group.

Five minutes later, each mouse was individually placed into a glassbeaker for observation, and the number of writhes occurring during thefollowing ten-minute period was counted.

A test compound was considered to have produced analgesia in a mouse if,in accordance with the conditions set forth above, and under the testcriteria employed for this assay, after the administration of 30 mg perkilogram of body weight of a compound of the present invention to themouse, the number of writhes elicited by a mouse injected with PBQ wasequal to, or less than, one-half the median number of writhes recordedfor the saline-treated control group of mice that day, as described byTaber in "Predictive Value of Analgesic Assays in Mice and Rats,"Advances in Biochemical Psychopharmacology, 8, 191 (1974).

The standard initial screening dose of a test compound employed in thisassay was 10 mpk per gram of body weight. If this initial screening doseof the test compound produced analgesia in seven of nine or ten mice,then the effect of additional doses of the test compound on the writhingresponse was evaluated, and then the ED₅₀ value (that dose of a compoundwhich produced analgesia in 50% of the mice to which the compound wasadministered) was generally calculated. A maximum likelihood functionwas used to determine the ED₅₀ value. (The slopes of the dose-responsecurves for all test compounds analyzed were compared as described byTallarida and Murray, Manual of Pharmacologic Calculations, Page 11(Springer Verlag, New York, 1981).

The results for the particular compounds of the present inventionanalyzed in this assay, and discussed in the examples identified belowwhich correspond thereto, are presented in Table 1 hereinbelow. Thecompounds of the present invention which were tested in this assay, andfor which results are presented in Table 1, correspond to the particularexamples specified in Table 1. The fractions indicate the number of miceout of nine or ten in which a test compound produced analgesia, and thewhole numbers are the calculated ED₅₀ values.

                  TABLE 1                                                         ______________________________________                                        Data Generated from the Writhing Assay                                        Compound Tested Intragastric                                                  ______________________________________                                        Example 3       2/10                                                          Example 5       4/10                                                          Example 7       6.8                                                           Example 9       9.7                                                           Example 11      1/10                                                          Example 13      9/10                                                          Example 15      6.4                                                           Example 17      5.1                                                           Example 19      2/9                                                           Example 20      4/10                                                          Example 22      3/10                                                          Exmaple 24      14.7                                                          Example 25      5/10                                                          Example 29      5/10                                                          Example 33      8/10                                                          Example 34      7/10                                                          Example 38      1/10                                                          Example 40      2/10                                                          Example 41      10/10                                                         Example 43      1/10                                                          Example 47      7/10                                                          Example 49      2/10                                                          Example 54      6/10                                                          Example 56      5/10                                                          Example 58      7/10                                                          Example 61      6/10                                                          Example 65      4/10                                                          Example 67      6/10                                                          ______________________________________                                    

(b) Prostaglandin (PGE) Antagonism Assay

In order to determine the effectiveness of several of the compounds ofthe present invention ("test compounds") as prostaglandin E₂antagonists, a prostaglandin antagonism assay was conducted, asdescribed below, to determine the ability of these compounds to inhibitprostaglandin E₂ -induced contractions of segments of guinea pig ileum.If a test compound inhibits prostaglandin E₂ -induced contractions, itsuggests that the compound functionally antagonizes prostaglandin E₂.

Male albino guinea pigs weighing 200 to 500 grams were sacrificed bycervical dislocation. The ilea were then quickly removed from the guineapigs and placed in a modified Tyrode solution, a solution which is knownto those skilled in the art, containing one-half of the usual amount ofmagnesium ions.

Segments of ileum about 2 cm long were then cut and mounted in a 10-mLtissue bath containing the modified Tyrode solution. The solution wasmaintained at 37° C. and aerated with a gaseous mixture of 95% oxygenand 5% carbon dioxide. Data for a control prostaglandin E₂ dose responsecurve plotting concentration of prostaglandin E versus the intensity ofcontractions, detected isotonically, was then obtained by experimentallyadjusting the dose of the prostaglandin E₂ being injected into thetissue bath, in a manner known by those of skill in the art.

Solutions or suspensions containing an initial concentration (3micromolar) of a test compound in modified Tyrode solution ("testsolutions/suspensions") were then separately substituted for the controlbath solution. Each test solution/suspension was then kept in constantcontact with the ileum tissue, except for brief periods to drain thebath in preparation for rinsing with fresh test solution/suspension. Asecond prostaglandin E₂ dose response curve was then generated forprostaglandin E₂ in the presence of a test compound.

A dose ratio (DR) of EC₅₀ doses was then calculated from the results ofeach test in a manner known by those of skill in the art. A control doseresponse curve (DRC) is produced in isolated segments of guinea pigileum mounted in an automated apparatus with six concentrations ofprostaglandin E₂. A solution or suspension of test compound issubstituted for the control bathing solution and is incubated for thirtyminutes. An additional prostaglandin E₂ dose response curve is producedin the presence of the test compound. A dose ratio is calculated fromthe EC₅₀ values obtained from duplicate replications on eachconcentration of the test compound. A concentration of test compound isjudged to be active if it produces a dose ratio significantly greaterthan that obtained in a series of blank treatments.

The results of this prostaglandin antagonism assay are presented inTable 2 below in terms of their dose ratio. The compounds of the presentinvention which were tested in this assay, and for which results arepresented in Table 2, correspond to the particular examples specified inTable 2.

                  TABLE 2                                                         ______________________________________                                        Data Generated from the Prostaglandin Antagonism Assay                        Compound Tested Dose Ratio                                                    ______________________________________                                        Example 3       1.5                                                           Example 5       2.4                                                           Example 7       5.1                                                           Example 9       1.4                                                           Example 13      1.6                                                           Example 15      2.1                                                           Example 17      3.1                                                           Example 19      6.0                                                           Example 20      8.0                                                           Example 22      3.0                                                           Exmaple 24      11.9                                                          Example 25      1.6                                                           Example 29      2.2                                                           Example 33      6.7                                                           Example 35      1.0                                                           Example 40      4.1                                                           Example 41      2.6                                                           Example 43      0.8                                                           Example 47      2.9                                                           Example 50      2.7                                                           Example 54      2.4                                                           Example 56      3.3                                                           Example 58      6.6                                                           Example 61      4.8                                                           Example 65      8.4                                                           Example 67      10.2                                                          Example 79      10                                                            Compound 81     32                                                            ______________________________________                                    

While the present invention has been described herein with somespecificity, and with reference to certain preferred embodimentsthereof, those of ordinary skill in the art will recognize numerousvariations, modifications and substitutions of that which has beendescribed which can be made, and which are within the scope and spiritof the invention. For example, effective dosages other than thepreferred ranges set forth hereinabove may be applicable as aconsequence of variations in the responsiveness of the animal beingtreated, dosage-related adverse effects, if any, and analogousconsiderations. Likewise, the specific pharmacological responsesobserved may vary according to, and depending upon, the particularactive compound selected, or whether there are present certainpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed. Such expected variations and/or differences inthe results are contemplated in accordance with the objects andpractices of the present invention. It is intended therefore that all ofthese modifications and variations be within the scope of the presentinvention as described and claimed herein, and that the invention belimited only by the scope of the claims which follow, and that suchclaims be interpreted as broadly as is reasonable.

What is claimed is:
 1. A compound having a structure: ##STR123## or apharmaceutically-acceptable salt thereof, wherein: X is oxygen, sulfur,##STR124## Y is hydrogen, halogen or hydroxy; Z is hydrogen or halogen;Ais alkylene or carbonyl; B is --CH or nitrogen; D is carbon or nitrogen;E is alkylene, carbonyl, alkyleneamino or alkylenecarbonyl; G ishydrogen, alkyl, cycloalkyl, alkoxy, aminoalkyl, aminocycloalkyl, aryl,alkylenearyl or aryl-substituted aryl; R is hydrogen or --CO₂ R¹ ; R¹ ishydrogen or alkyl; m is an integer of from 0 to 4; n is an integer offrom 0 to 4; r is 0 or 1; q is an integer of from 0 to 1; t is aninteger of from 0 to 1; and p is an integer of from 0 to 1;with theproviso that B and D cannot both be --CH, with the proviso that B cannotbe --CH when G is hydrogen, alkyl or cycloalkyl, with the proviso that mand n are not each 0, with the proviso that G is not alkyl or cycloalkylwhen X is sulfur, A is alkylene, B is --CH and D is nitrogen, with theproviso that G is not aminoalkyl or aminocycloalkyl when X is oxygen orsulfur, A is alkylene, B is nitrogen, R is hydrogen, D is carbon and ris 1; with the proviso that G is not hydrogen or alkyl when X is oxygenor sulfur, A is alkylene, B is nitrogen, D is carbon, E is alkylene andf is O or 1; and with the proviso that G is not hydrogen, alkyl orcycloalkyl when X is oxygen or sulfur, A is carbonyl, B is nitrogen, Eis alkylene and p is 0 or 1; and with the proviso that when q is 0 and tis 1, then the bond between the CH and D groups is a double bond.
 2. Acompound of claim 1 wherein X is oxygen.
 3. A compound of claim 2wherein Y is hydrogen.
 4. A compound of claim 3 wherein A is carbonyl.5. A compound of claim 4 wherein B is nitrogen.
 6. A compound of claim 5wherein R is --CO₂ R¹, q is 1 and t is
 1. 7. A compound of claim 6wherein R¹ is alkyl.
 8. A compound of claim 5 wherein R is --CO₂ R¹, qis 1 and t is
 0. 9. A pharmaceutical composition comprising apharmaceutically-acceptable carrier and a therapeutically-effectiveamount of a compound of claim
 1. 10. A method for treating pain in ananimal comprising administering to said animal atherapeutically-effective amount of a compound of claim
 1. 11. A methodfor treating diseases in an animal which are responsive toprostaglandin-E₂ antagonists comprising administering to said animal atherapeutically-effective amount of a compound of claim 1.